Gene expression biomarkers of laquinimod responsiveness

ABSTRACT

This invention provides a method of predicting clinical responsiveness to laquinimod therapy in a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome comprising evaluating expression of a biomarker in the subject. This invention also provides a method of treating said subject comprising determining whether the subject is a laquinimod-responder by evaluating expression of a biomarker. Also provided is laquinimod or a pharmaceutical composition comprising laquinimod for use in treating said subject, and a therapeutic package for use in dispensing to said subject, wherein the subject has been identified as a laquinimod-responder or expression of a biomarker in the subject is up-regulated or suppressed.

Throughout this application, various publications are referred to by first author and year of publication. Full citations for these publications are presented in a References section immediately before the claims. Disclosures of the publications cited in the References section in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as of the date of the invention described herein.

BACKGROUND

Multiple Sclerosis (MS) is a neurological disease affecting more than 1 million people worldwide. It is the most common cause of neurological disability in young and middle-aged adults and has a major physical, psychological, social and financial impact on subjects and their families, friends and bodies responsible for health care (EMEA Guideline, 2006).

A clinically isolated syndrome (CIS) is a single monosymptomatic attack suggestive of MS, such as optic neuritis, brain stem symptoms, and partial myelitis. Patients with CIS that experience a second clinical attack are generally considered to have clinically definite multiple sclerosis (CDMS). Various MS disease stages and/or types are described in Multiple Sclerosis Therapeutics (Duntiz, 1999). Among them, relapsing-remitting multiple sclerosis (RRMS) is the most common form at the time of initial diagnosis. Many subjects with RRMS have an initial relapsing-remitting course for 5-15 years, which then advances into the secondary progressive MS (SPMS) disease course. There are currently a number of disease-modifying medications approved for use in relapsing MS (RMS), which includes RRMS and SPMS (The Disease Modifying Drug Brochure, 2006). These include interferon beta 1-a (Avonex® and Rebif®), interferon beta 1-b (Betaseron®), glatiramer acetate (Copaxone®), mitoxantrone (Novantrone®), natalizumab (Tysabri®) and Fingolimod (Gilenya®). Immunosuppressants or cytotoxic agents are used in some subjects after failure of conventional therapies. However, the relationship between changes of the immune response induced by these agents and the clinical efficacy in MS is far from settled (EMEA Guideline, 2006).

Other therapeutic approaches include symptomatic treatment which refers to all therapies applied to improve the symptoms caused by the disease (EMEA Guideline, 2006) and treatment of acute relapses with corticosteroids. While steroids do not affect the course of MS over time, they can reduce the duration and severity of attacks in some subjects.

Laquinimod (LAQ)

Laquinimod (TV-5600) is a novel synthetic compound with high oral bioavailability which has been suggested as an oral formulation for the treatment of Multiple Sclerosis (MS) (Polman, 2005; Sandberg-Wollheim, 2005; Comi et al 2008). Laquinimod and its sodium salt form are described, for example, in U.S. Pat. No. 6,077,851. The mechanism of action of laquinimod is not fully understood.

Animal studies show it causes a Th1 (T helper 1 cell, produces pro-inflammatory cytokines) to Th2 (T helper 2 cell, produces anti-inflammatory cytokines) shift with an anti-inflammatory profile (Yang, 2004; Brück, 2011). Another study demonstrated (mainly via the NFkB pathway) that laquinimod induced suppression of genes related to antigen presentation and corresponding inflammatory pathways (Gurevich, 2010). Other suggested potential mechanisms of action include inhibition of leukocyte migration into the CNS, increase of axonal integrity, modulation of cytokine production, and increase in levels of brain-derived neurotrophic factor (BDNF) (Runström, 2002; Brück, 2011).

Laquinimod showed a favorable safety and tolerability profile in two phase III trials (Results of Phase III BRAVO Trial Reinforce Unique Profile of Laquinimod for Multiple Sclerosis Treatment; Teva Pharma, Active Biotech Post Positive Laquinimod Phase 3 ALLEGRO Results).

IUPAC: 5-chloro-N-ethyl-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide

As MS therapeutic options grow, the ability to identify subjects who will respond more favorably to therapy and specifically to laquinimod has become increasingly significant.

SUMMARY OF THE INVENTION

The subject invention provides a method of predicting clinical responsiveness to laquinimod therapy in subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome, the method comprising evaluating expression of a biomarker in the subject, so as to thereby predict clinical responsiveness to laquinimod, wherein the biomarker is a gene associated with inflammatory response, a gene associated with cellular movement, a gene associated with cell signaling, a gene associated with cell development, a gene associated with hematological system, or a combination thereof.

The subject invention provides a method of treating a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome with laquinimod, comprising the steps of: a) determining whether the subject is a laquinimod responder by evaluating expression of a biomarker in the subject, and b) administering to the subject an amount of laquinimod effective to treat the subject only if the subject is identified as a laquinimod responder, so as to thereby treat the subject, wherein the biomarker is a gene associated with inflammatory response, a gene associated with cellular movement, a gene associated with cell signaling, a gene associated with cell development, a gene associated with hematological system, or a combination thereof.

The subject invention also provides a method for treating a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome comprising the steps of: a) administering to the subject a therapeutically effective amount of laquinimod, b) determining whether the subject is a laquinimod responder by evaluating expression of a biomarker in the subject; and c) administering to the subject an amount of laquinimod effective to treat the subject only if the subject is identified as a laquinimod responder, or modifying the administration of laquinimod to the subject if the subject is not identified as a laquinimod responder, so as to thereby treat the subject, wherein the biomarker is a gene associated with inflammatory response, a gene associated with cellular movement, a gene associated with cell signaling a gene associated with cell development, a gene associated with hematological system, or a combination thereof.

The subject invention also provides laquinimod for use in treating a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome, wherein the subject has been identified as a laquinimod responder.

The subject invention also provides a pharmaceutical composition comprising an amount of laquinimod for use in treating a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome, wherein the subject has been identified as a laquinimod responder.

The subject invention also provides laquinimod for use in treating a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome, wherein expression of a biomarker in the subject is up-regulated and the biomarker is a gene associated with inflammatory response, a gene associated with cellular movement, a gene associated with cell signaling, a gene associated with cell development, a gene associated with hematological system, or a combination thereof.

The subject invention also provides a pharmaceutical composition comprising an amount of laquinimod for use in treating a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome, wherein expression of a biomarker in the subject is up-regulated and the biomarker is a gene associated with inflammatory response, a gene associated with cellular movement, a gene associated with cell signaling, a gene associated with cell development, a gene associated with hematological system, or a combination thereof.

The subject invention also provides laquinimod for use in treating a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome, wherein expression of a biomarker in the subject is suppressed and the biomarker is a gene associated with inflammatory response, a gene associated with cellular movement, a gene associated with cell signaling, a gene associated with cell development, a gene associated with hematological system, or a combination thereof.

The subject invention also provides a pharmaceutical composition comprising an amount of laquinimod for use in treating a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome, wherein expression of a biomarker in the subject is suppressed and the biomarker is a gene associated with inflammatory response, a gene associated with cellular movement, a gene associated with cell signaling, a gene associated with cell development, a gene associated with hematological system, or a combination thereof.

The subject invention also provides a therapeutic package for dispensing to, or for use in dispensing to, a subject identified as a laquinimod responder afflicted with multiple sclerosis or presenting a clinically isolated syndrome, which comprises: a) one or more unit doses, each such unit dose comprising an amount of laquinimod, and b) a finished pharmaceutical container therefor, said container containing said unit dose or unit doses, said container further containing or comprising labeling directing the use of said package in the treatment of said subject.

The subject invention also provides a therapeutic package for dispensing to, or for use in dispensing to, a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome, which comprises: a) one or more unit doses, each such unit dose comprising an amount of laquinimod, and b) a finished pharmaceutical container therefor, said container containing said unit dose or unit doses, said container further containing or comprising labeling directing the use of said package in the treatment of said subject, wherein expression of a biomarker in the subject is suppressed or up-regulated and the biomarker is a gene associated with inflammatory response, a gene associated with cellular movement, a gene associated with cell signaling, a gene associated with cell development, a gene associated with hematological system, or a combination thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Source of variation in data set (point 4) before (FIG. 1A) and after (FIG. 1B) normalization.

FIG. 2: PCA analysis. FIG. 2A—PCA analysis based on 43 genes passed FDR criteria after 6 month of treatment. FIG. 2B PCA analysis based on 1564 genes passed FDR in combined 6 and 24 months treatment data. Red dots represent patients at baseline, blue after treatment.

FIG. 3: TGFB canonical pathway. Green color represents suppressed genes from combined 6 and 24 month LAQ related gene expression signature overlaid with TGFB.

FIG. 4: Immunomodulatory effects of TGFB in MS. Paradoxical effects TGFB in multiple sclerosis is shown (according to Mirshafiey et al., 2009).

FIG. 5: Expression of TGFB1 in PBMCs of RRMS patients following treatment with LAQ. Protein samples (30 mg) were prepared from phenol/ethanol fractions of PBMCs derived from patients after 6 month of LAQ treatment (+) and compared to PBMCs samples of the same patients before treatment (−) (FIGS. 5A and 5C). From each sample 30 ug was separated on 10% SDS-PAGE. Blots were incubated with Rabbit a-TGFb1 (1:250) and mouse Tubulin (1:500). The signal intensities of a protein band and its surrounding background were scanned for each protein and quantified by using Quantity One 4.6.9 software (Bio-Rad Laboratories, Hercules, Calif.). The resultant background-subtracted values of protein expression were normalized to those of Tubulin and then plotted as the relative protein levels for each patient with or without LAQ treatment (FIGS. 5B and 5D).

FIG. 6: Expression of PAI-1 (Serpine 1) in PBMCs of patients following treatment with LAQ. Protein samples were prepared from phenol/ethanol fractions of PBMCs derived from patients after 6 month of LAQ treatment (+) and compare to PBMCs samples of the same patients before treatment (−) (A). From each sample 30 mg was separated on 10% SDS-PAGE. Blots were incubated with Rabbit a-PAI-1 (1:500) and mouse Tubulin (1:500). The signal intensities of a protein band and its surrounding background were scanned for each protein and quantified by using Quantity One 4.6.9 software. The resultant background-subtracted values of protein expression were normalized to those of Tubulin and then plotted as the relative protein levels for each patient with or without LAQ treatment (B).

FIG. 7: Profiles of PTCRA, TGFB1 and TGFB1 related genes PF4 and CSGP5 under LAQ treatment.

FIG. 8: FIG. 8A and FIG. 8B show proposed mechanism of LAQ effect on PBMC of RRMS patients. FIG. 8C shows LAQ down-regulates leukocyte extravasation in RRMS patients. LAQ can inhibit infiltration of inflammatory cells to the CNS by direct suppression of genes associated with leukocyte extravasation or via suppression of TGFb superfamily and inflammatory cytokines.

FIG. 9: FIG. 9A shows LAQ treatment for six months in RRMS patients down-regulates multiple genes associated with TGFb and NFkB signaling, pro inflammatory cytokines, cell adhesion and migration. Shaded color represents down regulated genes. FIG. 9B shows LAQ effects in RRMS patients after six months of treatment demonstrate down-regulation of multiple genes associated with TGFb and NFkB signaling, pro inflammatory cytokines, cell adhesion and migration. Grey color represents down regulated genes and white color depicts genes with no change in their expression level.

FIG. 10: Expression of TGFb, ITGB1 and CXCR1 in RRMS patients treated with LAQ. Protein extracts were prepared from PBMCs samples derived from RRMS patients before treatment (black bars) and compared to PBMCs samples of the same patients after six months of LAQ treatment (white bars). The signal intensity of a protein bands were quantified by Quantity One 4.6.9 software. The resultant background-subtracted values of protein expression were normalized to those of Tubulin and then calculated as the relative protein levels for each patient before or after LAQ treatment. The blot images in A, B and C are representative of two out of five analyzed patients showing down regulation of TGFb, ITGB1 and CXCR1, respectively as also quantified by densitometry of bands analyzed from five patients. Data are presented as mean±SEM. Statistically significant differences are marked in graphs (n=5, paired one-tailed t-test).

DETAILED DESCRIPTION OF THE INVENTION

The subject invention provides a method of predicting clinical responsiveness to laquinimod therapy in a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome, the method comprising evaluating expression of a biomarker in the subject, so as to thereby predict clinical responsiveness to laquinimod, wherein the biomarker is a gene associated with inflammatory response, a gene associated with cellular movement, a gene associated with cell signaling, a gene associated with cell development, a gene associated with hematological system, or a combination thereof.

In one embodiment of the present invention, the method further comprises predicting positive clinical responsiveness to laquinimod if the biomarker is up-regulated in the subject. In another embodiment, the subject is naïve to laquinimod.

In another embodiment of the present invention, the method further comprises predicting positive clinical responsiveness to laquinimod if the biomarker suppressed in the subject. In another embodiment, the subject has previously received periodic laquinimod administration. In another embodiment, the expression of the biomarker is suppressed in comparison to expression of said biomarker of the patient at baseline.

In one embodiment, the subject has received periodic laquinimod administration for at least one month. In another embodiment, the subject has received periodic laquinimod administration for at least 6 months. In another embodiment, the subject has received periodic laquinimod administration for at least 12 months. In another embodiment, the subject has received periodic laquinimod administration for at least 24 months.

In one embodiment, the gene associated with inflammatory response is a gene associated with or involved in TGFb signaling, IL-12 signaling, the pathway of adhesion of phagocytes, chemotaxis of neutrophils, transmigration of leukocytes, caveolar mediated endocytosis, clathrin mediated endocytosis, and/or leukocyte extravasation signaling.

In another embodiment, the gene associated with cellular movement is a gene associated with or involved in adhesion and migration of phagocytes, chemotaxis of neutrophils, transmigration of leukocytes, invasion of cells, adhesion of cells, and/or leukocyte extravasation signaling.

In another embodiment, the gene associated with cell signaling is a gene associated with or involved in the pathway of adhesion of cells and/or neurotransmission.

In another embodiment, the gene associated with cell development is a gene associated with or involved in the pathway of G protein coupled receptor signaling, arachidonic acid metabolism and/or TGFβ signaling.

In another embodiment, the gene associated with hematological system is a gene associated with or involved in the pathway of aggregation of blood platelets, activation of blood platelets, aggregation of blood cells, coagulation of blood, intrinsic prothrombin activation pathway and/or coagulation system.

In another embodiment, the gene is TNFSF4, SELP, ITFA8, ITGB1/3/5, CXCL5/7, a BMP6 gene, ITGA2/8, ITGβ1/3/4/5/6, ITGBL1, MMP16/24/26/28, ADAM12/18/22, IL-1/1R/5/8/13/20/22R, IL-9/11/12/36, TNFRSF11A/B, IFNA4/8/10/17, TGβ, LTBP4, MEK1/2, TGFβ type 1 receptor, type II BMPR, smad1/2/3/4/5/6/8, PAI-1, CCL19, IKKg, LTBP1 or a combination thereof.

In one embodiment of any one of the methods, uses, pharmaceutical composition or packages described herein, the gene is ITGB1/3/5, CXCL5/7, BMP6, ITGA2/8, ITGB1/3/4/5/6, ITGBL1, MMP16/24/26/28, ADAM12/18/22, IL-5/20/22, IL-9/36, TNFRSF11A/B, TGβ, LTBP4, MEK1/2, Smad2/3/4, PAI-1, SELP, ITFA8, ITGB1/3/5, CXCL5/7, BMP6, ITGA2/8, ITGB1/3/4/5/6, ITGBL1, MMP16/24/26/28, ADAM12/18/22, IL-5/13/20/22, IL-9/11/36, TNFRSF11A/B, TGβ, LTBP4, MEK1/2, Smad1/2/3/4/5/6/8, PAI-1, CCL19, IKKg, LTBP1, Alpha tubulin, BMP4/7, MIS, TCF2, IL5R, IL13R, IL20R, ITGB2, NKTR, TEF, CLSTN2, LUC7L2, FABP7, TPTE, FSTL1, SF3B1, LIMS1, PDE5A, XPNPEP1, C5orf4, SPANXB1, SPANXB2, SPANXF1, KRT20, TBC1D1, GRHL2, C5orf4, SEPT6, KIAA1199, SSX2IP, TPM1, CDC14B, USP47, MMRN1, CTNNAL1, SMOX, ALOX12, GLRA3, CA2, GUCY1B3, RFPL1, CLEC1B, GNG11, TSPAN32, RGS10, CALD1, PRKAR2B, CYP4F11, CLCA3P, CELSR3, CDC14B, TPM1, SEPT6, PRKG1, MAX, CCDC93, ARMCX6, LOC653354, TUBB2B, HIST1H2AJ, MFAP3L, LIMS1, GNB5, GPRASP1, SRRT, C1orf116, FBXO7, PPM1A, GUCY1B3, CTDSPL, GNAS, IGF2BP3, TPM1, HIST1H2BK, DLG4, WDR48, CALD1, LOC157627, GNB5, ZNF415, ASAP2, PSD3, GNAS, POPDC3, NRGN, ABLIM3, XYLT1, PTGIS, ARHGEF10, PDGFA, PGRMC1, HIST1H2AC, GNAS, CLDN5, MFAP3L, PGRMC1, MYST3, CAPRIN1, CALD1, FBXW7, DNM3, CD84, PRPF4B, RBM25, WASF3, GRAP2, SPARC, TAL1, NENF, XK, GP1BA, HLA-E, CA5A, LYVE1, MARCH6, NAT8B, TRIM58, RET, SDPR, TBXA2R, TMED10, APBA2, MYL9, POU1F1, H2BFS, HIST1H2BK, FAM12B, VCL, GSPT1, ALDOB, LOC150776, SMPD4, SLC37A1, SPARC, GNAS, TAS2R4, CALM3, POM121, POM121C, GRIK2, GREM1, TNNC2, EPS15L2, ENDOD1, RGS6, SF3B1, TMSB15A, ZBTB20, FUT9, ATP9A, MAX, HIST1H2AI, BAT2D1, ABL1, SNCA, GFI1B, CTSA, SNX13, RPA1, FLNA, XPNPEP1, KIF2A, ZBTB33, PSMD11, UBE2N, FOLR1, TSC22D1, PCNP, CELSR3, ACSBG1, RNF11, SEMA3E, MARCH2, PCDH24, SUPT5H, HLA-E, EGF, HLA-C, FLNA, CDK2AP1, LEPROT, SH3TC2, TUBA4A, MTMR1, TF, PRKD1, NAPIL1, DAB2, FUCA1, HIP1, THPO, MAP1B, PARVB, GP1BB, SEPT5, GJA4, PTGS1, GUCY1A3, HIST1H2AG, GNAS, LRBA, HYAL3, GP6, IGHG1, CYP2A13, CDC14B, MAX, KDM2A, CALD1, GNAZ, C19orf22, ARHGAP6, RHOC, RBX1, GP1BB, SEPT5, PRDX6, PRB4, FLNA, HIST1H2BF, RHBDF2, NUP205, SYT1, EGFL8, PPT2, TUBB1, TMC6, FLJ11292, NAP1L1, ALDH1A3, CSNK1E, PRUNE, COL4A3, ZNF221, ILF3, CABP5, RPA1, ARF1, HIST1H2BI, PTGS1, PRKAA1, GNB5, HIST2H4A, HIST2H4B, CYB5R3, TNS1, DCT, GMPR, ABI3BP, GNAS, SASH1, AAK1, XPO6, CTSL2, QSER1, MAP1LC3B, TBX6, CABP2, MRE11A, MAPRE2, TMC6, BDKRB2, MGLL, HRASLS, WHAMML1, WHAMML2, CLU, STC1, C6orf54, PABPN1, PDLIM1, CLU, PHF20, UBL4A, RNF115, HGD, RASGRP2, PNN, SAPS3, SFI1, GOLGA2, HIST2H2BE, SGEF, HGD, DUS1L, MPP1, HLA-E, GRB14, MMD, ZFHX4, CSNK1G2, HIST1H2BE, MPDZ, B2M, TBXA2R, CTDSPL, SNCA, CD99, POLS, MPL, HIST1H3F, SFRS8, NR5A2, ZMYM2, C6orf10, TMEM40, RNF43, PRUNE, MSH6, PLCB4, PARVB, TOX3, PKNOX1, RUFY1, SNCA, C10orfB1, PDGFA, ASMT, HMGB1, CCDC90A, PROS1, hCG_1757335, RAP1B, MTSS1, GNRHR, LRRN3, MCM3AP, PLOD2, NAP1L1, PLOD2, HOXD13 CASKIN2, MFAP5, PITX2, SNCA, MYLK, PBX1, PRDX6, H3F3A, H3F3B, LOC440926, TMEM158, TRIM58, FSTL1, SNCA, TNS1, ATP1B1, C5orf4, LRP12, CTNNAL1, GEM, KIAA1466, ALDH1A2, MAP4K3, SNCA, RAB6B, PSD3, RIPK2, RAMP3, CALD1, CYP2E1, PSD3, PDLIM7, COBLL1, FUT3, SMOX, TGM2, LRRC50, CST6, OR7A17, C6orf145, DLEU2, DLEU2L, CPT2, HGF, TNS1, SPRY1, PLOD2, CD80, KYNU, BCAT1, NHLH1, AHCTF1, HOXA10, MTMR3, VAC14, CLCF1, FGF5, TAL1, SAMD14, ELL2, CHN1, SLC7A1, GRK5, PARD3, VPS37B, CYP2B6, CYP2B7P1, MALL, ALX4, SOX15, KRT5, ESPL1, STARD8, PSD3, KIAA0195, MYO9B, HIP1R, LOC100294412, EFNB1, ERN1, RHD, MFAP3L, PLA1A, POFUT2, C8orf39, CRYBB2, CYP4A11, PVRL2, CLCNKB, MRAS, NFIB, FKSG2, SLC11A2, FZR1, ZNF550, GLP1R, SLC19A1, RTN2, PAPOLA, STC1, GK, EXOSC6, RAPSN, HFE, EHD2, RIOK3, UBE2I, C15orf2, DMD, PRLH, MAP2K2, TP63, DACH1, PPP5C, SLC26A1, NUDT7, KCNJ12, ENTPD7, SLC26A1, PRRG3, RGS6, ZBED2, FICD, ARHGAP1, ARHGDIA, SDHB, AMHR2, ABCA4, TCF20, BGN, CASP7, LPAR4, GNA12, CYP2W1, RAX, C4A, C4B, LOC100292046, LOC100294156, PXN, ESR2, MYL10, EFS, TFF3, SRPK1, LOC441601, BIRC5, CCT8L2, PPAP2B, CMA1, APOA2, KDELR2, ASCL3, RUNX1, BUB1, SLC6A8, HNRNPC, HNRNPCL1, LOC440563, LOC649330, RIBC2, CLIC4, RAB17, SCML2, SPINLW1, ANK1, EDA2R, HTR4, CDC42EP4, KANK2, ANK1, SYN1, DUX3, DUX4, FRG2C, HPX-2, LOC100134409, LOC652119, LOC653543, LOC653544, LOC653545, LOC728410, PKNOX2, MLLT4, APOA2, PENK, GNAT1, FURIN, SEMA6A, EGFL6, HRH1, TSPAN1, DBC1, TRPC7, GPR52, HAMP, PRSS2, GPR107, FLJ11292, FLJ20184, B4GALT1, NKX3-1, ASIP, EFCAB6, GPR20, CA5A, PLK4, TAAR5, SRPX2, CNTD2, AZGP1, TIMP3, RGS6, ADARB1, DYNC1I1, C10orf10, PDIA2, PITX3, HOXC13, LPAR3, CTRC, CTSL2, MUC8, AQP5, UGT1A1, UGT1A10, UGT1A4, UGT1A6, UGT1A8, UGT1A9, KCNQ2, CYP2A13, ZNF155, KIAA0892, ATP2A2, FGF5, FGF18, FUT2, SHROOM2, PRSS3, CREB3L1, MGAT2, PLCE1, MLXIPL, OR10H3, ABCB11, CD84, ARHGEF4, ORC1L, PCIF1, CD177, C1orf116, IFT122, C11orf20, DUSP13, C6orf208, PLA2G5, PRAMEF1, PRAMEF2, CYP4F8, KCNA1, MFAP4, SLC4A3, IL1RAPL1, SERPINE1, ZCCHC14, POLR3G, C16orf68, FLJ14100, SMCHD1, ASCL1, FOXA2, SLC23A2, KLK13, MTSS1L, DNMT3L, RREB1, DNMBP, PKLR, C1orf106, CCDC134, MTSS1, CCDC40, HOXB1, SCNN1B, SEMA4G, RAPGEFL1, MAGEL2, PLSCR2, CHD2, PLCD1, C1orf116, CHRNA2, MBP, CDC42BPA, MYF6, PI15, LOC440895, SBF1, MAST1, GLT8D2, ERBB3, LOH3CR2A, AMH, HR, RDH8, PAWR, DRD3, CCT8, PRELP, SPOCK3, EPS8L3, NXN, SEMA4G, P2RY1, AVL9, TEK, MOGAT2, KLK7, MT1E, MT1H, MT1M, CLDN18, RHBDF2, SIX1, INPP5A, KCNMB3, MAP2K5, GPD1, LPO, LOC729143, MPRIP, WNT7A, RARG, CDH7, MBNL2, RASGRP2, RBMY2FP, MASP1, CASR, EGR4, APOC2, HECW1, HOXB3, IRF5, NNMT, AOC2, ESRRG, LPIN1, ACOT11, CCDC33, MBD2, ZNF323, NTRK2, TMEM151B, GPLD1, LENEP, HNF1B, NXPH3, ALDH1A3, PHF20L1, CKM, PARD6B, CRYGB, HAB1, LARGE, RAB40C, MPL, CHIT1, METTL10, DUS4L, PNLIPRP1, ELL, ST8SIA5, GRIN2B, MC4R, RTDR1, HDAC6, KCNJ13, CPSF1, SPANXC, CNOT4, LAMA2, SLC1A6, ABCA2, KLK11, GFRA3, CYP3A4, SLC1A3, ATP2B2, APBB2, VPS45, GHRHR, HOXD4, PRPH, ADCY2, LEFTY2, CYP1B1, PCP4, C8B, RANBP3, PDE6H, TRIM1S, VGLL1, TRIM3, CRKL, ADH7, PSG3, GPR153, MFAP2, FGF13, NAPA, ALDH3A1, MCM10, TLE4, ITPR3, CCDC87, C9orf7, ACTC1, OBSL1, MAP2, CRYM, RNF122, SST, HLA-DRB6, SLC22A17, HSPG2, HIP1, GRIK2, UNKL, GPR144, KIR3DX1, NARFL, UCP3, PLXNA2, BTN1A1, ERCC4, CIITA, EGFR, KRT33A, CLTB, B3GALT5, AP3M2, GJC1, MYO3A, ARHGAP1, PPP2R3A, CLIC4, C20orf195, SIGLEC8, GPRC5A, CACNB1, MYL10, PRLR, OR2S2, NCR2, CHAF1B, EYA3, CDS1, FBXL18, ACTL6B, ZNF821, C16orf71, HBBP1, PLXNA1, CDC45L, MTCP1, PLCB4, PLVAP, PROX1, CYP3A43, IGHG1, RECQL5, IDUA, DLGAP4, PLXNB1, HSD17B14, FOXP3, C19orf26, EPB41L1, RBBP9, GJB4, UPK1B, CYP19A1, LOC55908, CLDN18, C2orf72, NTRK3, NRXN2, SPDEF, IGH@, IGHD, IGHG1, IGHM, LOC100289944, VSIG6, ACRV1, PHLDB1, SORBS1, HAPLN2, FABP3, EFS, ACVR1B, CHST3, UGT2A1, UGT2A2, TAF1, MT4, MFAP3, ETV5, UBQLN3, TBX10, GJB1, ABO, SPINK5, ATAD4, CDH11, CARD14, ALPP, ALPPL2, CBL, LRP4, CDKL2, SSX3, DSG2, SLC45A2, LAMA4, WFDC8, HTR7, EFNB3, TUBB2B, OR7E19P, PMS2L4, ASAP3, FRZB, PDLIM4, PVT1, TFR2, AHI1, TAF4, ADAMTSL2, CLDN4, KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL5A, KIR2DL5B, KIR2DS1, KIR2DS2, KIR2DS4, KIR2DS5, KIR3DL2, KIR3DL3, KIR3DP1, LOC727787, RAPGEF5, CRMP1, LDB3, F11, USP46, IBSP, SLC9A3, FLRT3, TRIM17, FGF17, CAMK1G, GLYR1, CSH1, NTF3, ABHD6, TRIM15, OR52A1, FGFR2, ORAI2, C17orf53, GLP1R, SLIT1, TP63, DDR1, CFTR, DIO2, LETM1, ACSM5, ACTA1, NPR1, KCND3, POPDC3, DNAH3, SPDEF, CLEC4M, SLC30A3, NAGLU, AAK1, DHX34, NNAT, AKAP9, ICMT, FAM189A1, C10orf81, MYOZ1, PKNOX2, MGC31957, PRDM11, RET, IGHG1, XPNPEP2, NTRK2, SLC25A10, NR1I2, GRM8, OR3A3, GIPR, PAH, PACRG, CLN8, ZNF215, TRIO, TTLL5, GRM1, PRKG1, HHLA1, LAMA3, SLC37A4, HOXC11, SLCO5A1, CA10, RRBP1, SOD3, NTRK3, CYR61, STRA6, SLC6A11, CNOT4, ATN1, BCAP29, NOVA2, RELN, LAMC2, RAD51, PRSS7, DCBLD2, TACR2, RAB11B, OR2J2, VSNL1, IFNA17, DPYSL4, MGC2889, RRBP1, POLQ, OR1A2, PURA, AIF1, CBS, NECAB2, PRKCE, NOX1, IHH, EXO1, GPRIN2, PDX1, GPR12, FAM188A, HS3ST3B1, ASCL1, ZNF484, CSH1, BCAN, DDN, DUOX2, MORN1, SLC39A2, CLCN7, RUNX2, TTYH1, ZNF280B, PAX3, LZTS1, SLC8A2, HAB1, KIF1A, ARL4D, UGT2B15, NACA2, THRB, C6orf15, GPR176, WSCD1, PLXNB3, CADM3, HAP1, CYP1A2, SPAM1, IL22RA1, CDC2L5, IRX5, PPFIA2, KDELR3, CEACAM7, KCMF1, DUOX1, CDC27, HIST2H2AA3, CAV3, APOA4, NPR3, PRG3, TBC1D22B, TUSC3, RIMS2, CYP4F12, TBXA2R, HBEGF, PSG9, PYGO1, RASGRF1, SCN2A, KLHL1, DTNB, GREM1, SNCG, C22orf24, PALM, COBLL1, DNPEP, MNS1, NFATC4, DLC1, HSPC072, MCAM, CA12, CSHL1, RPAIN, COL5A2, UGT1A8, UGT1A9, IGH@, IGHA1, IGHG1, IGHG2, IGHG3, IGHM, LOC100126583, LOC100290036, LOC100290320, LOC100293211, LOC652494, ACSM5, ALOX12P2, ERBB4, CLDN16, CIB2, GALR3, MSMB, FABP7, ATXN3, KCNJ5, TRDN, CYP3A43, BAZ2A, ACCN4, SILV, DGCR14, SEMA6C, DIO2, PTHLH, LEP, PDZRN3, RGSL1, GJA4, SLC22A6, RASGRF1, MAPRE2, PVRL1, AKAP1, POMP, SOX21, DNAH9, HOXC5, SERHL2, KIAA0485, ITSN1, B4GALT1, NEK2, NUPR1, CCDC93, EPO, CRABP2, TYRO3, GOLGA2, SEMA3F, BFSP2, NCAM1, FOLH1, SSX2, TMPRSS4, DCN, LPHN3, POU4F3, CEACAM5, BCL3, EXTL3, CCNA1, DDR2, PAX8, SOX5, POU3F1, PEX16, NUP62, SIGLEC11, ALDOB, GPC3, IGFALS, WDR25, FGF1, OSR2, ARID1A, GYPA, KLK13, PARVB, LILRB5, RIMS2, C19orf21, HOXD1, PRSS3, FLT1, ATP6V1C1, LOX, CRYBB3, CA12, PRKG2, MASP1, LOC728395, LOC728403, TSPY1, PDCD1, GGTLC1, AQP8, KRT16, AICDA, BRD8, C1orf95, OR3A2, PFKFB2, FRZB, PAK3, MEIS2, ZSCAN2, MYH7, VWA1, LSAMP, SRC, UGT1 A1, UGT1A10, UGT1A3, UGT1A4, UGT1A5, UGT1A6, UGT1A7, UGT1A8, UGT1A9, DIO1, TADA3L, NFASC, CALCRL, NBLA00301, MAB21L1, FBXO42, COL10A1, CFB, SNX7, FOXN1, SRY, HLF, CLCA3P, DAZ1, DAZ2, DAZ3, DAZ4, GPR3, TMPRSS11E, EMID1, KCNMB2, MUC5AC, SORT1, HIF3A, MAPK4, TCP11L1, ZZEF1, DCAF7, DMWD, CLCA2, VAC14, CSPG5, STMN2, MLLT4, GALNT14, FGF12, MFAP5, SUMO3, HTR3A, GDF5, TSSK1B, CYP2A7P1, MARK1, ATP1B2, TBX6, PAX8, IL1R1, RALYL, OR2B2, TAAR3, C12orf32, IGHG1, LOC642131, DICER1, GLRA3, PPARD, HSPA4L, WNT2, VIPR2, CYP2C9, SRPX2, IGSF1, ALPK3, TFPI, KCNS3, MARCH8, FRMD4B, TACR3, FIGF, PDCD6, TNN, SPANXB1, SPANXB2, SPANXF1, RHBDD3, SPP2, PDE10A, ZNF224, FGL1, PGAM2, CADM4, APOBEC2, SLC9A5, GNAT1, ARHGEF16, SMARCA2, DNAH9, RBM26, WNT2B, KCNK2, NPBWR2, SP2, TMPRSS11D, DENND2A, TNIP3, STC1, DOCK6, ADAM5P, SYDE1, TNPO2, LRTM1, USH1C, PDE12, SRCAP, OR10J1, OR2H2, KCNJ8, RP11-257K9.7, DOCK5, TPD52L1, PAEP, GGA2, PHLDA3, HES2, MLL, CHRNA6, CIB2, PTPRF, TM7SF4, DAZ1, DAZ2, DAZ3, DAZ4, ALX1, OR2F1, OR2F2, PLAT, HGC6.3, WNT11, PGK2, SNAI2, COL4A6, PRUNE2, ANKS1B, LOC81691, FERMT2, TIMP3, CST8, CAPN6, IDUA, GPR32, AKR1B10, GRHL2, FBXO24, HSF4, IGHG1, HCN2, LRP12, ARHGEF15, UGT1A1, UGT1A10, UGT1A7, UGT1A8, GUCA2A, ITIH1, EGFR, UGT1A1, UGT1A10, UGT1A3, UGT1A4, UGT1A5, UGT1A6, UGT1A7, UGT1A8, UGT1A9, MYOG, TMSB15A, TLX1, EDNRA, LOC100289791, MDFI, ZER1, MYH15, CDH20, GPR63, LOC440345, LOC440354, LOC595101, LOC641298, SMG1, HOXC10, KRTAP1-1, ARSD, CPLX3, LMAN1 L, IFNA4, ABCC1, SEMA3E, MRE11A, C1QL1, LIPF, TRIM9, BBOX1, LRRC17, WNT2B, CYP3A4, SI, ANO3, OBSL1, CHRD, MSX2, PSG1, FAM107A, LRRC37B2, ANKLE2, PAX2, UNC5B, ADCYAP1R1, HFE, SYT1, GJC2, LOC100293871, FGF8, ACRV1, NRXN1, GDPD2, RGS4, CELA2A, IFNW1, MLNR, RNF17, LAD1, GLRA2, RASL12, MAGOH2, C6orf54, ZNF214, IKBKG, AP4E1, ZNRF4, OSBPL10, C1orf175, TTC4, PCDHB3, ADRBK1, ITSN1, XAGE1A, XAGE1B, XAGE1C, XAGE1D, XAGE1E, CDH22, FARP2, MYT1, TNC, MUC5AC, SLC6A15, PP14571, SMR3A, SMR3B, RXRG, SNX1, GLP1R, C6orf155, ATP1A2, TFAP4, PNPLA2, DIRAS3, ANO2, TACSTD2, MCM3AP, IL13RA2, TRIM10, RTEL1, PRRX2, TSHB, TIMELESS, FMO1, KIF18A, KIAA1199, CALB2, MFAP3L, PTGER3, EPAS1, SQSTM1, TSPY1, CPM, DLGAP1, CYP4F11, TLX3, PCDHA10, TAOK2, ERC1, TBX2, KALRN, DICER1, PAPPA, KIF5A, DNAJC22, OTUB1, KIAA1644, SEZ6L2, PCNXL2, HMHB1, ERG, SNTB2, GJA5, AGTR2, GJA3, GCK, LRRC61, CNTF, ZFP91, ZFP91-CNTF, PDLIM4, MPPED2, IFNA10, ACTN2, VGLL1, GJA9, LDLR, ANK2, COL1A1, TIMP3, OTOF, AGXT, GLI2, TRMT61A, FOXD2, TMEM212, DENND2A, B3GALT1, SPAG11A, PRDM4, TF, ELF5, GSC2, EPB41 L4B, GYG2, LYZL6, DCHS2, OBP2A, OBP2B, ANGPTL3, MYH11, NES, SLC17A1, RBM15B, CSH1, HTR5A, CYP3A7, HTR2A, KCNV2, TOX3, CLOCK, MAGEA6, FAM12A, COL4A3, S1PR2, NAT8, ACE2, SLC22A6, SLC13A2, MYH4, APBB2, RAP1QGAP, SHOX2, SLCO1A2, ETV1, MAGEA12, PLA2G6, ADRA1A, SYT5, GPR161, SEMA3F, CYP3A43, HOMER2, KCNJ5, PPL, COL17A1, CSHL1, C9orf116, PARK2, UGT2B15, CDK6, FAM174B, CELA2A, CELA2B, SPDEF, EPB41, GAB1, SMR3A, PDE60, COL5A1, ABCA6, DMD, CYLC2, CIDEA, RAG2, HIST1H2BN, FMO6P, MAOA, ANKRD53, HAPLN1, MT1M, EHD2, GAD2, CRISP2, CSN2, SULT1C2, PCDHGA3, SSX3, FGFR2, GPR161, ATN1, CHD5, A4GALT, MYBPH, CSHL1, NCAPH2, CAPN9, CNGB1, BCAM, DRD5, NR5A2, TEF, ELAVL2, DGKB, HTR7P, RHAG, GH2, COL4A6, BMP7, SOSTDC1, SOX14, TAS2R9, LPHN2, MAP1A, OSGIN2, SLC10A2, FAM13C, EMX1, FLJ40330, CHI3L1, CDH16, SPRR1A, LOX, CALCB, GABBR2, CPB2, RASL11B, CCDC81, RUNX1, CPA1, CLCNKA, CLCNKB, FHL5, THSD7A, TFAP2C, SPAG11B, CAP2, PODNL1, SSX4, SSX4B, G6PC, RPE65, TMEM222, KDR, CHP2, GPR64, TPM2, TCEB3B, E2F5, IL5RA, AOC3, ABCF3, CPN2, ACE, NRP2, INPP5J, SMAD9, FAM155A, GART, PIR, ZNF467, ITSN2, NR1D1, THRA, RP11-35N6.1, LAMB1, EPHB3, PLA2R1, RAPGEF4, DNAJC8, ARSJ, TRIM49, GC, CDH2, ATXN3L, BTF3L1, BICC1, FAM186A, PTPRF, TRPC4, TCL6, CYP4A22, FUT6, MUC1, DKFZP434B2016, LOC643313, LDHA, LOC100131613, TRIM3, MLLT10, DZIP1, ANKRD34C, BUB1, CSPG5, FBLN1, GAD2, CLDN1, CHRNA3, SCN11A, TEX11, IL20RA, AKAP5, KBTBD10, MSTN, TLL2, NACAD, UNC93A, PTGER1, OLAH, NHLH2, SERPINA6, KRT17, KCNMA1, PRKCA, STS, LAMA1, GPR88, ACTN2, TREH, AKAP4, DKK4, PRICKLE3, IRS4, TRPV4, PCDH11Y, APBB2, SLCO2A1, DRD2, MTMR7, ZNF471, TF, NRIP2, ST6GALNAC5, COMT, PAH, LRRC19, PRKAR1B, HPR, PRDM5, NCRNA00120, LOC79999, ITSN2, CACNB2, GPR98, PREX2, FAM182B, LAMA4, ARVCF, HAS2, YOD1, PPP2R3A, COL4A1, RBM12B, GSTA3, FAM66D, OR10H2, PTHLH, ZNF674, KRT19, ACCN2, COL6A1, LOC100288442, LOC100289169, LOC728888, LOC729602, NPIPL2, NPIPL3, PDXDC2, SLC37A1, ATP6V1B1, ABI3BP, HR44, ZNF324B, ZNF584, HOXD13, ADH6, IFNA8, MYOZ2, NFATC4, ADAMTS7, FOXL1, GPR17, SLC18A3, MYH6, BOK, FGA, TEAD4, GRM1, EDNRA, C8orf79, METTL7A, FOLH1, RAD54L, SOX11, CNOT3, NTS, MAPK12, DOCK6, DNAJC6, HS3ST3A1, LOC728395, TSPY1, TSPY3, PTH, LAMB4, ALDOB, FLG, MLANA, UBE2D4, LOC100287483, KRT20, POU1F1, SLCO1B3, CLTA, MECOM, C8orf71, SULT2A1, C6orf10, SLC27A6, PRKD1, SYNPO2L, THPO, GABRR1, CFTR, PPP2R3A, DCBLD2, ANP32A, ANP32C, ANP32D, LOC723972, XYLT1, STAB1, STAB1, SASH1, PID1, FUCA1, SASH1, LRRN3, LRRN3 or a combination thereof.

In another embodiment, the gene is ITGB1/3/5, CXCL5/7, BMP6, ITGA2/8, ITGB1/3/4/5/6, ITGBL1, MMP16/24/26/28, ADAM12/18/22, IL-5/20/22, IL-9/36, TNFRSF11A/B, TGβ, LTBP4, MEK1/2, Smad2/3/4, PAI-1, SELP, ITFA8, ITGB1/3/5, CXCL5/7, BMP6, ITGA2/8, ITGB1/3/4/5/6, ITGBL1, MMP16/24/26/28, ADAM12/18/22, IL-5/13/20/22, IL-9/11/36, TNFRSF11A/B, TGβ, LTBP4, MEK1/2, Smad1/2/3/4/5/6/8, PAI-1, CCL19, IKKg, LTBP1 or a combination thereof. In another embodiment, the gene is SELP, ITFA8, ITGB1/3/5, CXCL5/7, BMP6, ITGA2/8, ITGB1/3/4/5/6, ITGBL1, MMP16/24/26/28, ADAM12/18/22, IL-1/1R/5/8/13/20/22, IL-9/11/12/36, TNFRSF11A/B, IFNA4/8/10/17, TGβ, LTBP4, MEK1/2, Smad1/2/3/4/5/6/8, PAI-1, CCL19, IKKg, LTBP1 or a combination thereof.

In one embodiment of any one of the methods, uses, pharmaceutical composition or packages described herein, the gene is TNFSF4, ITGB1/3/5, CXCL5/7, BMP6, ITGA2/8, ITGB1/3/4/5/6, ITGBL1, MMP16/24/26/28, ADAM12/18/22, IL-1/5/8/20/22, IL-9/12/36, TNFRSF11A/B, IFNA4/8/10/17, TGβ, LTBP4, MEK1/2, TGFβ type 1 receptor, Smad2/3/4, PAI-1, TNFSF4, SELP, ITFA8, ITGB1/3/5, CXCL5/7, a BMP6 gene, ITGA2/8, ITGβ1/3/4/5/6, ITGBL1, MMP16/24/26/28, ADAM12/18/22, IL-1/1R/5/8/13/20/22R, IL-9/11/12/36, TNFRSF11A/B, IFNA4/8/10/17, TGβ, LTBP4, MEK1/2, TGFβ type 1 receptor, type II BMPR, smad1/2/3/4/5/6/8, PAI-1, CCL19, IKKg, LTBP1, IL8R (CXCR1/2), Alpha tubulin, BMP2/4/7, MIS, TCF2, LFA-1, VLA-4, IL5R, IL13R, IL20R, ITGB2, IFN gamma, TNF alpha, NKTR, TEF, CLSTN2, LUC7L2, FABP7, TPTE, FSTL1, SF31B1, LIMS1, PDE5A, XPNPEP1, C5orf4, SPANXB1, SPANXB2, SPANXF1, KRT20, TBC1D1, GRHL2, C5orf4, SEPT6, KIAA1199, SSX2IP, TPM1, CDC14B, USP47, MMRN1, CTNNAL1, SMOX, ALOX12, GLRA3, CA2, GUCY1B3, RFPL1, CLEC1B, GNG11, TSPAN32, RGS10, CALD1, PRKAR2B, CYP4F11, CLCA3P, CELSR3, CDC14B, TPM1, SEPT6, PRKG1, MAX, CCDC93, ARMCX6, LOC653354, TUBB2B, HIST1H2AJ, MFAP3L, LIMS1, GNB5, GPRASP1, SRRT, C1orf116, FBXO7, PPM1A, GUCY1B3, CTDSPL, GNAS, IGF2BP3, TPM1, HIST1H2BK, DLG4, WDR48, CALD1, LOC157627, GNB5, ZNF415, ASAP2, PSD3, GNAS, POPDC3, NRGN, ABLIM3, XYLT1, PTGIS, ARHGEF10, PDGFA, PGRMC1, HIST1H2AC, GNAS, CLDN5, MFAP3L, PGRMC1, MYST3, CAPRIN1, CALD1, FBXW7, DNM3, CD84, PRPF4B, RBM25, WASF3, GRAP2, SPARC, TAL1, NENF, XK, GP1BA, HLA-E, CA5A, LYVE1, MARCH6, NAT8B, TRIM58, RET, SDPR, TBXA2R, TMED10, APBA2, MYL9, POU1F1, H2BFS, HIST1H2BK, FAM12B, VCL, GSPT1, ALDOB, LOC150776, SMPD4, SLC37A1, SPARC, GNAS, TAS2R4, CALM3, POM121, POM121C, GRIK2, GREM1, TNNC2, EPS15L2, ENDOD1, RGS6, SF3B1, TMSB15A, ZBTB20, FUT9, ATP9A, MAX, HIST1H2AI, BAT2D1, ABL1, SNCA, GFI1B, CTSA, SNX13, RPA1, FLNA, XPNPEP1, KIF2A, ZBTB33, PSMD11, UBE2N, FOLR1, TSC22D1, PCNP, CELSR3, ACSBG1, RNF11, SEMA3E, MARCH2, PCDH24, SUPT5H, HLA-E, EGF, HLA-C, FLNA, CDK2AP1, LEPROT, SH3TC2, TUBA4A, MTMR1, TF, PRKD1, NAP1L1, DAB2, FUCA1, HIP1, THPO, MAP1B, PARVB, GP1BB, SEPT5, GJA4, PTGS1, GUCY1A3, HIST1H2AG, GNAS, LRBA, HYAL3, GP6, IGHG1, CYP2A13, CDC14B, MAX, KDM2A, CALD1, GNAZ, C19orf22, ARHGAP6, RHOC, RBX1, GP1BB, SEPT5, PRDX6, PRB4, FLNA, HIST1H2BF, RHBDF2, NUP205, SYT1, EGFL8, PPT2, TUBB1, TMC6, FLJ11292, NAP1L1, ALDH1A3, CSNK1E, PRUNE, COL4A3, ZNF221, ILF3, CABP5, RPA1, ARF1, HIST1H2BI, PTGS1, PRKAA1, GNB5, HIST2H4A, HIST2H4B, CYB5R3, TNS1, DCT, GMPR, ABI3BP, GNAS, SASH1, AAK1, XPO6, CTSL2, QSER1, MAP1LC3B, TBX6, CABP2, MRE11A, MAPRE2, TMC6, BDKRB2, MGLL, HRASLS, WHAMML1, WHAMML2, CLU, STC1, C6orf54, PABPN1, PDLIM1, CLU, PHF20, UBL4A, RNF115, HGD, RASGRP2, PNN, SAPS3, SFI1, GOLGA2, HIST2H2BE, SGEF, HGD, DUS1L, MPP1, HLA-E, GRB14, MMD, ZFHX4, CSNK1G2, HIST1H2BE, MPDZ, B2M, TBXA2R, NGFRAP1, CTDSPL, SNCA, CD99, POLS, MPL, HIST1H3F, SFRS8, NR5A2, ZMYM2, C6orf10, TMEM40, RNF43, PRUNE, MSH6, PLCB4, PARVB, TOX3, PKNOX1, RUFY1, SNCA, C10orf81, PDGFA, ASMT, HMGB1, CCDC90A, PROS1, hCG_1757335, RAP1B, MTSS1, GNRHR, LRRN3, MCM3AP, PLOD2, NAPIL1, PLOD2, HOXD13 CASKIN2, MFAP5, PITX2, SNCA, MYLK, PBX1, PRDX6, EIF2AK1, H3F3A, H3F3B, LOC440926, TMEM158, TRIM58, FSTL1, SNCA, TNS1, ATP1B1, C5orf4, LRP12, CTNNAL1, GEM, KIAA1466, ALDH1A2, MAP4K3, SNCA, RAB6B, PSD3, RIPK2, RAMP3, CALD1, CYP2E1, PSD3, PDLIM7, COBLL1, FUT3, SMOX, TGM2, LRRC50, CST6, OR7A17, C6orf145, DLEU2, DLEU2L, CPT2, HGF, TNS1, SPRY1, PLOD2, CD80, KYNU, BCAT1, NHLH1, AHCTF1, HOXA10, MTMR3, VAC14, CLCF1, FGF5, TAL1, SAMD14, ELL2, CHN1, SLC7A1, GRK5, PARD3, VPS37B, CYP2B6, CYP2B7P1, MALL, ALX4, SOX15, KRT5, ESPL1, STARD8, PSD3, KIAA0195, MYO9B, HIP1R, LOC100294412, EFNB1, ERN1, RHD, MFAP3L, PLA1A, POFUT2, C8orf39, CRYBB2, CYP4A11, PVRL2, CLCNKB, MRAS, NFIB, FKSG2, SLC11A2, FZR1, ZNF550, GLP1R, SLC19A1, RTN2, PAPOLA, STC1, GK, EXOSC6, RAPSN, HFE, EHD2, RIOK3, UBE2I, C15orf2, DMD, PRLH, MAP2K2, TP63, DACH1, PPP5C, SLC26A1, NUDT7, KCNJ12, ENTPD7, SLC26A1, PRRG3, RGS6, ZBED2, FICD, ARHGAP1, ARHGDIA, SDHB, AMHR2, ABCA4, TCF20, BGN, CASP7, LPAR4, GNA12, CYP2W1, RAX, C4A, C4B, LOC100292046, LOC100294156, ELAVL4, PXN, ESR2, MYL10, EFS, TFF3, SRPK1, LOC441601, BIRC5, CCT8L2, PPAP2B, CMA1, APOA2, KDELR2, ASCL3, RUNX1, BUB1, SLC6A8, HNRNPC, HNRNPCL1, LOC440563, LOC649330, RIBC2, CLIC4, RAB17, SCML2, SPINLW1, ANK1, EDA2R, HTR4, CDC42EP4, KANK2, ANK1, SYN1, DUX3, DUX4, FRG2C, HPX-2, LOC100134409, LOC652119, LOC653543, LOC653544, LOC653545, LOC728410, PKNOX2, MLLT4, APOA2, PENK, GNAT1, FURIN, SEMA6A, EGFL6, HRH1, TSPAN1, DBC1, TRPC7, MDM2, GPR52, HAMP, PRSS2, GPR107, FLJ11292, FLJ20184, B4GALT1, NKX3-1, ASIP, EFCAB6, GPR20, CA5A, PLK4, TAAR5, SRPX2, CNTD2, AZGP1, TIMP3, RGS6, ADARB1, DYNC1I1, C10orf10, PDIA2, PITX3, HOXC13, LPAR3, CTRC, CTSL2, MUC8, AQP5, UGT1A1, UGT1A10, UGT1A4, UGT1A6, UGT1A8, UGT1A9, KCNQ2, CYP2A13, ZNF155, KIAA0892, ATP2A2, FGF5, FGF18, FUT2, SHROOM2, PRSS3, CREB3L1, MGAT2, PLCE1, MLXIPL, OR10H3, ABCB11, CD84, ARHGEF4, ORC1L, PCIF1, CD177, C1orf116, IFT122, C11orf20, DUSP13, C6orf208, PLA2G5, PRAMEF1, PRAMEF2, CYP4F8, KCNA1, MFAP4, C6, SLC4A3, IL1RAPL1, SERPINE1, ZCCHC14, POLR3G, C16orf8, FLJ14100, SMCHD1, ASCL1, FOXA2, SLC23A2, KLK13, MTSS1L, DNMT3L, RREB1, DNMBP, PKLR, C1orf106, CCDC134, MTSS11, CCDC40, HOXB1, SCNN1B, SEMA4G, RAPGEFL1, MAGEL2, PLSCR2, CHD2, PLCD1, C1orf116, CHRNA2, MBP, CDC42BPA, MYF6, PI15, LOC440895, SBF1, MAST1, GLT8D2, ERBB3, LOH3CR2A, AMH, HR, RDH8, PAWR, DRD3, CCT8, PRELP, SPOCK3, EPS8L3, NXN, SEMA4G, P2RY1, AVL9, TEK, MOGAT2, KLK7, MT1E, MT1H, MT1M, CLDN18, RHBDF2, SIX1, INPP5A, KCNMB3, MAP2K5, GPD1, LPO, LOC729143, MPRIP, WNT7A, RARG, CDH7, MBNL2, RASGRP2, RBMY2FP, MASP1, CASR, EGR4, APOC2, HECW1, HOXB3, IRF5, NNMT, AOC2, ESRRG, LPIN1, ACOT11, CCDC33, MBD2, ZNF323, NTRK2, TMEM151B, GPLD1, LENEP, HNF1B, NXPH3, ALDH1A3, PHF20L1, CKM, PARD6B, CRYGB, HAB1, LARGE, RAB40C, MPL, CHIT1, METTL10, DUS4L, PNLIPRP1, ELL, ST8SIA5, GRIN2B, MC4R, RTDR1, HDAC6, KCNJ13, CPSF1, SPANXC, CNOT4, LAMA2, SLC1A6, ABCA2, KLK11, GFRA3, CYP3A4, SLC1A3, ATP2B2, APBB2, VPS45, GHRHR, HOXD4, PRPH, ADCY2, LEFTY2, CYP1B1, PCP4, C8B, RANBP3, PDE6H, TRIM15, VGLL1, TRIM3, CRKL, ADH7, PSG3, GPR153, MFAP2, FGF13, NAPA, ALDH3A1, MCM10, TLE4, ITPR3, CCDC87, C9orf7, ACTC1, OBSL1, MAP2, CRYM, RNF122, SST, HLA-DRB6, SLC22A17, HSPG2, HIP1, GRIK2, UNKL, GPR144, KIR3DX1, NARFL, UCP3, PLXNA2, BTN1A1, ERCC4, CIITA, EGFR, KRT33A, CLTB, B3GALT5, AP3M2, GJC1, MYO3A, ARHGAP1, PPP2R3A, CLIC4, C20orf195, SIGLEC8, GPRC5A, CACNB1, MYL10, PRLR, OR2S2, NCR2, CHAF1B, EYA3, CDS1, FBXL18, ACTL6B, ZNF821, C16orf71, HBBP1, PLXNA1, CDC45L, MTCP1, PLCB4, PLVAP, PROX1, CYP3A43, IGHG1, RECQL5, IDUA, DLGAP4, PLXNB1, HSD17B14, FOXP3, C19orf26, EPB41L1, RBBP9, GJB4, UPK1B, CYP19A1, LOC55908, CLDN18, C2orf72, NTRK3, NRXN2, SPDEF, IGH@, IGHD, IGHG1, IGHM, LOC100289944, VSIG6, ACRV1, PHLDB1, SORBS1, HAPLN2, FABP3, EFS, ACVR1B, CHST3, UGT2A1, UGT2A2, TAF1, MT4, MFAP3, ETV5, UBQLN3, TBX10, GJB1, ABO, SPINK5, ATAD4, CDH11, CARD14, ALPP, ALPPL2, CBL, LRP4, CDKL2, SSX3, DSG2, SLC45A2, LAMA4, WFDC8, HTR7, EFNB3, TUBB2B, OR7E19P, PMS2L4, ASAP3, FRZB, PDLIM4, PVT1, TFR2, AHI1, TAF4, ADAMTSL2, CLDN4, KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL5A, KIR2DL5B, KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS4, KIR2DS5, KIR3DL2, KIR3DL3, KIR3DP1, LOC727787, RAPGEF5, CRMP1, LDB3, F11, USP46, PTN, IBSP, SLC9A3, FLRT3, TRIM17, FGF17, CAMK1G, GLYR1, CSH1, NTF3, ABHD6, TRIM15, OR52A1, FGFR2, ORAI2, C17orf53, GLP1R, SLIT1, TP63, DDR1, CFTR, DIO2, LETM1, ACSM5, ACTA1, NPR1, KCND3, POPDC3, DNAH3, SPDEF, CLEC4M, SLC30A3, NAGLU, AAK1, DHX34, NNAT, AKAP9, ICMT, FAM189A1, C10orf81, MYOZ1, PKNOX2, MGC31957, PRDM11, RET, IGHG1, XPNPEP2, NTRK2, SLC25A10, NR1I2, GRM8, OR3A3, GIPR, PAN, PACRG, CLN8, ZNF215, TRIO, TTLL5, GRM1, PRKG1, HHLA1, LAMA3, PTN, SLC37A4, HOXC11, SLCO5A1, CA10, RRBP1, SOD3, NTRK3, CYR61, STRA6, SLC6A11, CNOT4, ATN1, BCAP29, NOVA2, RELN, LAMC2, RAD51, PRSS7, DCBLD2, TACR2, RAB11B, OR2J2, VSNL1, IFNA17, DPYSL4, MGC2889, RRBP1, POLQ, OR1A2, PURA, AIF1, CBS, NECAB2, PRKCE, NOX1, INH, EXO1, GPRIN2, PDX1, GPR12, FAM188A, HS3ST3B1, ASCL1, ZNF484, CSH1, BCAN, DDN, DUOX2, MORN1, SLC39A2, CLCN7, RUNX2, TTYH1, ZNF280B, PAX3, LZTS1, SLC8A2, HAB1, KIF1A, ARL4D, UGT2B15, NACA2, THRB, C6orf15, GPR176, WSCD1, PLXNB3, CADM3, HAP1, CYP1A2, SPAM1, IL22RA1, CDC2L5, IRX5, PPFIA2, KDELR3, CEACAM7, KCMF1, DUOX1, CDC27, HIST2H2AA3, CAV3, APOA4, NPR3, PRG3, TBC1D22B, TUSC3, RIMS2, CYP4F12, TBXA2R, HBEGF. PSG9, PYGO1, RASGRF1, SCN2A, KLHL1, DTNB, GREM1, SNCG, C22orf24, PALM, COBLL1, DNPEP, MNS1, NFATC4, DLC1, HSPC072, MCAM, CA12, CSHL1, RPA1N, COL5A2. UGT1A8, UGT1A9, IGH@, IGHA1, IGHG1, IGHG2, IGHG3, IGHM, LOC100126583, LOC100290036, LOC100290320, LOC100293211, LOC652494, TGFB2, ACSM5, ALOX12P2, ERBB4, CLDN16, CIB2, GALR3, MSMB, FABP7, ATXN3, KCNJ5, TRDN, CYP3A43, BAZ2A, ACCN4, SILV, DGCR14, SEMA6C, DIO2, PTHLH, LEP, PDZRN3, RGSL1, GJA4, SLC22A6, RASGRF1, MAPRE2, PVRL1, AKAP1, POMP, SOX21, DNAH9, HOXC5, SERHL2, KIAA0485, ITSN1, B4GALT1, NEK2, NUPR1, CCDC93, EPO, CRABP2, TYRO3, GOLGA2, SEMA3F, BFSP2, NCAM1, FOLH1, SSX2, TMPRSS4, DCN, LPHN3, POU4F3, CEACAM5, BCL3, EXTL3, CCNA1, DDR2, PAX8, SOX5, POU3F1, PEX16, 1L4I1, NUP62, SIGLEC11, ALDOB, GPC3, IGFALS, WDR25, FGF1, OSR2, ARID1A, GYPA, KLK13, PARVB, LILRB5, RIMS2, C19orf21, HOXD1, PRSS3, FLT1, ATP6V1C1, LOX, CRYBB3, CA12, PRKG2, MASP1, LOC728395, LOC728403, TSPY1, PDCD1, GGTLC1, AQP8, IL1F9, KRT16, AICDA, BRD8, C1orf95, OR3A2, PFKFB2, FRZB, PAK3, MEIS2, ZSCAN2, MYH7, VWA1, LSAMP, SRC, UGT1A1, UGT1A10, UGT1A3, UGT1A4, UGT1A5, UGT1A6, UGT1A7, UGT1A8, UGT1A9, DIO1, TADA3L, NFASC, CALCRL, NBLA00301, MAB21L1, FBXO42, COL10A1, CFB, SNX7, FOXN1, SRY, HLF, CLCA3P, DAZ1, DAZ2, DAZ3, DAZ4, GPR3, TMPRSS11E, EMID1, KCNMB2, MUC5AC, SORT1, HIF3A, MAPK4, TCP11L1, ZZEF1, DCAF7, DMWD, CLCA2, VAC14, CSPG5, STMN2, MLLT4, GALNT14, FGF12, MFAP5, SUMO3, HTR3A, GDF5, TSSK1B, CYP2A7P1, MARK1, ATP1B2, TBX6, PAX8, IL1R1, RALYL, OR2B2, TAAR3, C12orf32, IGHG1, LOC642131, DICER1, GLRA3, PPARD, HSPA4L, WNT2, VIPR2, CYP2C9, SRPX2, IGSF1, ALPK3, TFPI, KCNS3, MARCH8, FRMD4B, TACR3, FIGF, PDCD6, TNN, SPANXB1, SPANXB2, SPANXF1, RHBDD3, SPP2, PDE10A, ZNF224, FGL1, PGAM2, CADM4, APOBEC2, SLC9A5, GNAT1, ARHGEF16, SMARCA2, DNAH9, RBM26, WNT2B, KCNK2, NPBWR2, SP2, TMPRSS11D, DENND2A, TNIP3, STC1, DOCK6, ADAM5P, SYDE1, TNPO2, LRTM1, USH1C, PDE12, SRCAP, OR10J1, OR2H2, KCNJ8, RP11-257K9.7, DOCK5, TPD52L1, PAEP, GGA2, PHLDA3, HES2, MLL, PTN, CHRNA6, CIB2, PTPRF, TM7SF4, DAZ1, DAZ2, DAZ3, DAZ4, ALX1, OR2F1, OR2F2, PLAT, HGC6.3, WNT11, PGK2, SNAI2, COL4A6, PRUNE2, ANKS1B, LOC81691, FERMT2, TIMP3, CST8, CAPN6, IDUA, GPR32, AKR1B10, GRHL2, FBXO24, HSF4, IGHG1, HCN2, LRP12, ARHGEF15, UGT1A1, UGT1A10, UGT1A7, UGT1A8, GUCA2A, MDK, ITIH1, EGFR, UGT1A1, UGT1A10, UGT1A3, UGT1A4, UGT1A5, UGT1A6, UGT1A7, UGT1A8, UGT1A9, MYOG, TMSB15A, TLX1, EDNRA, LOC100289791, MDFI, ZER1, MYH15, CDH20, GPR63, LOC440345, LOC440354, LOC595101, LOC641298, SMG1, HOXC10, KRTAP1, ARSD, CPLX3, LMAN1L, IFNA4, ABCC1, SEMA3E, MRE11A, C1QL1, LIPF, TRIM9, BBOX1, LRRC17, WNT2B, CYP3A4, SI, ANO3, OBSL1, CHRD, MSX2, PSG1, FAM107A, LRRC37B2, ANKLE2, PAX2, UNC5B, ADCYAP1R1, HFE, SYT1, GJC2, LOC100293871, FGF8, ACRV1, NRXN1, GDPD2, RGS4, CELA2A, IFNW1, MLNR, RNF17, LAD1, GLRA2, RASL12, MAGOH2, C6orf54, ZNF214, IKBKG, AP4E1, ZNRF4, OSBPL10, C1orf175, TTC4, PCDHB3, ADRBK1, ITSN1, XAGE1A, XAGE1B, XAGE1C, XAGE1D, XAGE1E, CDH22, FARP2, MYT1, TNC, MUC5AC, SLC6A15, PP14571, SMR3A, SMR3B, RXRG, SNX1, GLP1R, C6orf155, ATP1A2, TFAP4, PNPLA2, DIRAS3, ANO2, TACSTD2, MCM3AP, IL13RA2, TRIM10, RTEL1, PRRX2, TSHB, TIMELESS, FMO1, KIF18A, KIAA1199, CALB2, MFAP3L, PTGER3, EPAS1, SQSTM1, TSPY1, CPM, DLGAP1, CYP4F11, TLX3, PCDHA10, TAOK2, ERC1, TBX2, KALRN, DICER1, PAPPA, KIF5A, DNAJC22, OTUB1, KIAA1644, SEZ6L2, PCNXL2, HMHB1, ERG, SNTB2, GJA5, AGTR2, GJA3, GCK, LRRC61, CNTF, ZFP91, ZFP91-CNTF, PDLIM4, MPPED2, IFNA10, ACTN2, VGLL1, GJA9, LDLR, ANK2, COL1A1, TIMP3, OTOF, AGXT, GLI2, TRMT61A, FOXD2, TMEM212, DENND2A, B3GALT1, SPAG11A, PRDM4, TF, ELF5, GSC2, EPB41L4B, GYG2, LYZL6, DCHS2, OBP2A. OBP2B, ANGPTL3, MYH11, NES, SLC17A1, RBM15B, CSH1, HTR5A, CYP3A7, HTR2A, KCNV2, TOX3, CLOCK, MAGEA6, FAM12A, COL4A3, S1PR2, NAT8, ACE2, SLC22A6, SLC13A2, MYH4, APBB2, RAP1GAP, SHOX2, SLCO1A2, ETV1, MAGEA12, PLA2G6, ADRA1A, SYT5, GPR161, SEMA3F, CYP3A43, HOMER2, KCNJ5, PPL, COL17A1, CSHL1, C9orf116, PARK2, UGT2B15, CDK6, FAM174B, CELA2A, CELA2B, SPDEF, EPB41, GAB1, SMR3A, PDE6G, COL5A1, ABCA6, DMD, CYLC2, CIDEA, RAG2, HIST1H2BN, FMO6P, MAOA, ANKRD53, HAPLN1, MT1M, EHD2, GAD2, CRISP2, CSN2, SULT1C2, PCDHGA3, SSX3, FGFR2, GPR161, ATN1, CHD5, A4GALT, MYBPH, CSHL1, NCAPH2, CAPN9, CNGB1, BCAM, DRD5, NR5A2, TEF, ELAVL2, DGKB, HTR7P, RHAG, GH2, COL4A6, BMP7, SOSTDC1, SOX14, TAS2R9, LPHN2, MAP1A, OSGIN2, SLC10A2, FAM13C, EMX1, FLJ40330, CHI3L1, CDH16, SPRR1A, LOX, CALCB, GABBR2, CPB2, RASL11B, CCDC81, RUNX1, CPA1, CLCNKA, CLCNKB, FHL5, THSD7A, TFAP2C, SPAG11B, CAP2, PODNL1, SSX4, SSX4B, G6PC, RPE65, TMEM222, KDR, CHP2, GPR64, TPM2, TCEB3B, E2F5, IL5RA, AOC3, ABCF3, CPN2, ACE, NRP2, INPP5J, SMAD9, FAM155A, GART, PIR, ZNF467, ITSN2, NR1D1, THRA, RP11-35N6.1, LAMB1, EPHB3, PLA2R1, RAPGEF4, DNAJC8, ARSJ, TRIM49, GC, IL12B, CDH2, ATXN3L, BTF3L1, BICC1, FAM186A, PTPRF, TRPC4, TCL6, CYP4A22, FUT6, MUC1, DKFZP434B2016, LOC643313, LDHA, LOC100131613, TRIM3, MLLT10, DZIP1, ANKRD34C, BUB1, CSPG5, FBLN1, GAD2, CLDN1, CHRNA3, SCN11A, TEX11, IL20RA, AKAP5, KBTBD10, MSTN, TLL2, NACAD, UNC93A, PTGER1, OLAH, NHLH2, SERPINA6, KRT17, KCNMA1, PRKCA, STS, LAMA1, GPR88, ACTN2, TREH, AKAP4, DKK4, PRICKLE3, IRS4, TRPV4, PCDH11Y, APBB2, SLCO2A1, DRD2, MTMR7, ZNF471, TF, NRIP2, ST6GALNAC5, COMT, PAH, LRRC19, PRKAR1B, HPR, PRDM5, NCRNA00120, LOC79999, ITSN2, CACNB2, GPR98, PREX2, FAM182B, LAMA4, ARVCF, HAS2, YOD1, PPP2R3A, COL4A1, RBM12B, GSTA3, FAM66D, OR10H2, PTHLH, ZNF674, KRT19, ACCN2, COL6A1, LOC100288442, LOC100289169, LOC728888, LOC729602, NPIPL2, NPIPL3, PDXDC2, SLC37A1, ATP6V1B1, PTN, ABI3BP, HR44, ZNF324B, ZNF584, HOXD13, ADH6, IFNA8, MYOZ2, NFATC4, ADAMTS7, FOXL1, GPR17, SLC18A3, MYH6, BOK, FGA, TEAD4, GRM1, EDNRA, C8orf79, METTL7A, FOLH1, RAD54L, SOX11, CNOT3, NTS, MAPK12, DOCK6, DNAJC6, HS3ST3A1, LOC728395, TSPY1, TSPY3, PTH, LAMB4, ALDOB, FLG, MLANA, UBE2D4, LOC100287483, KRT20, POU1F1, SLCO1B3, CLTA, MECOM, C8orf71, SULT2A1, C6orf10, SLC27A6, PRKD1, SYNPO2L, THPO, GABRR1, CFTR, PPP2R3A, DCBLD2, ANP32A, ANP32C, ANP32D, LOC723972, XYLT1, STAB1, STAB1, SASH1, PID1, FUCA1, SASH1, LRRN3, LRRN3 or any combination thereof.

In another embodiment, the gene is TNFSF4, ITGB1/3/5, CXCL5/7, BMP6, ITGA2/8, ITGB1/3/4/5/6, ITGBL1, MMP16/24/26/28, ADAM12/18/22, IL-1/5/8/20/22, IL-9/12/36, TNFRSF11A/B, IFNA4/8/10/17, TGβ, LTBP4, MEK1/2, TGFβ type 1 receptor, Smad2/3/4, PAI-1, TNFSF4, SELP, ITFA8, ITGB1/3/5, CXCL5/7, a BMP6 gene, ITGA2/8, ITGβ1/3/4/5/6, ITGBL1, MMP6/24/26/28, ADAM12/18/22, IL-1/1R/5/8/13/20/22R, IL-9/11/12/36, TNFRSF11A/B, IFNA4/8/10/17, TGβ, LTBP4, MEK1/2, TGFβ type 1 receptor, type II BMPR, smad1/2/3/4/5/6/8, PAI-1, CCL19, IKKg, LTBP1 or any combination thereof. In yet another embodiment, the gene is TNFSF4, ITGB1/3/5, CXCL5/7, BMP6, ITGA2/8, ITGB1/3/4/5/6, ITGBL1, MMP16/24/26/28, ADAM12/18/22, IL-1/5/8/20/22, IL-9/12/36, TNFRSF11A/B, IFNA4/8/10/17, TGβ, LTBP4, MEK1/2, TGFβ type 1 receptor, Smad2/3/4, PAI-1 or any combination thereof.

The subject invention also provides a method of treating a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome with laquinimod, comprising the steps of: a) determining whether the subject is a laquinimod responder by evaluating expression of a biomarker in the subject, and b) administering to the subject an amount of laquinimod effective to treat the subject only if the subject is identified as a laquinimod responder, so as to thereby treat the subject, wherein the biomarker is a gene associated with inflammatory response, a gene associated with cellular movement, a gene associated with cell signaling, a gene associated with cell development, a gene associated with hematological system, or a combination thereof.

The subject invention also provides a method for treating a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome comprising the steps of: a) administering to the subject a therapeutically effective amount of laquinimod, b) determining whether the subject is a laquinimod responder by evaluating expression of a biomarker in the subject; and c) administering to the subject an amount of laquinimod effective to treat the subject only if the subject is identified as a laquinimod responder, or modifying the administration of laquinimod to the subject if the subject is not identified as a laquinimod responder, so as to thereby treat the subject, wherein the biomarker is a gene associated with inflammatory response, a gene associated with cellular movement, a gene associated with cell signaling, a gene associated with cell development, a gene associated with hematological system, or a combination thereof.

In one embodiment, the subject is identified as a laquinimod responder if the biomarker is up-regulated in the subject. In another embodiment, the subject is identified as a laquinimod responder if the biomarker is suppressed in the subject.

In one embodiment, the gene associated with inflammatory response is a gene associated with or involved in TGFb signaling, IL-12 signaling, the pathway of adhesion of phagocytes, chemotaxis of neutrophils, transmigration of leukocytes, caveolar mediated endocytosis, clathrin mediated endocytosis, and/or leukocyte extravasation signaling.

In another embodiment, the gene associated with cellular movement is a gene associated with or involved in adhesion and migration of phagocytes, chemotaxis of neutrophils, transmigration of leukocytes, invasion of cells, adhesion of cells, and/or leukocyte extravasation signaling.

In another embodiment, the gene associated with cell signaling is a gene associated with or involved in the pathway of adhesion of cells and/or neurotransmission.

In another embodiment, the gene associated with cell development is a gene associated with or involved in the pathway of G protein coupled receptor signaling, arachidonic acid metabolism and/or TGFβ signaling.

In another embodiment, the gene associated with hematological system is a gene associated with or involved in the pathway of aggregation of blood platelets, activation of blood platelets, aggregation of blood cells, coagulation of blood, intrinsic prothrombin activation pathway and/or coagulation system.

In another embodiment, the gene is TNFSF4, SELP, ITFA8, ITGB1/3/5, CXCL5/7, a BMP6 gene, ITGA2/8, ITGβ1/3/4/5/6, ITGBL1, MMP16/24/26/28, ADAM12/18/22, IL-1/1R/5/8/13/20/22R, IL-9/11/12/36, TNFRSF11A/B, IFNA4/8/10/17, TGβ, LTBP4, MEK1/2, TGFβ type 1 receptor, type II BMPR, smad1/2/3/4/5/6/8, PAI-1, CCL19, IKKg, LTBP1 or a combination thereof.

In one embodiment of any one of the methods, uses, pharmaceutical composition or packages described herein, the gene is ITGB1/3/5, CXCL5/7, BMP6, ITGA2/8, ITGB1/3/4/5/6, ITGBL1, MMP16/24/26/28, ADAM12/18/22, IL-5/20/22, IL-9/36, TNFRSF11A/B, TGβ, LTBP4, MEK1/2, Smad2/3/4, PAI-1, SELP, ITFA8, ITGB1/3/5, CXCL5/7, BMP6, ITGA2/8, ITGB1/3/4/5/6, ITGBL1, MMP16/24/26/28, ADAM12/18/22, IL-5/13/20/22, IL-9/11/36, TNFRSF11A/B, TGβ, LTBP4, MEK1/2, Smad1/2/3/4/5/6/8, PAI-1, CCL19, IKKg, LTBP1, Alpha tubulin, BMP4/7, MIS, TCF2, IL5R, IL13R, IL20R, ITGB2, NKTR, TEF, CLSTN2, LUC7L2, FABP7, TPTE, FSTL1, SF3B1, LIMS1, PDE5A, XPNPEP1, C5orf4, SPANXB1, SPANXB2, SPANXF1, KRT20, TBC1D1, GRHL2, C5orf4, SEPT6, KIAA1199, SSX2IP, TPM1, CDC14B, USP47, MMRN1, CTNNAL1, SMOX, ALOX12, GLRA3, CA2, GUCY1B3, RFPL1, CLEC1B, GNG11, TSPAN32, RGS10, CALD1, PRKAR2B, CYP4F11, CLCA3P, CELSR3, CDC14B, TPM1, SEPT6, PRKG1, MAX, CCDC93, ARMCX6, LOC653354, TUBB2B, HIST1H2AJ, MFAP3L, LIMS1, GNB5, GPRASP1, SRRT, C1orf116, FBXO7, PPM1A, GUCY1B3, CTDSPL, GNAS, IGF2BP3, TPM1, HIST1H2BK, DLG4, WDR48, CALD1, LOC157627, GNB5, ZNF415, ASAP2, PSD3, GNAS, POPDC3, NRGN, ABLIM3, XYLT1, PTGIS, ARHGEF10, PDGFA, PGRMC1, HIST1H2AC, GNAS, CLDN5, MFAP3L, PGRMC1, MYST3, CAPRIN1, CALD1, FBXW7, DNM3, CD84, PRPF4B, RBM25, WASF3, GRAP2, SPARC, TAL1, NENF, XK, GP1BA, HLA-E, CA5A, LYVE1, MARCH6, NAT8B, TRIM58, RET, SDPR, TBXA2R, TMED10, APBA2, MYL9, POU1F1, H2BFS, HIST1H2BK, FAM12B, VCL, GSPT1, ALDOB, LOC150776, SMPD4, SLC37A1, SPARC, GNAS, TAS2R4, CALM3, POM121, POM121C, GRIK2, GREM1, TNNC2, EPS15L2, ENDOD1, RGS6, SF3B1, TMSB15A, ZBTB20, FUT9, ATP9A, MAX, HIST1H2AI, BAT2D1, ABL1, SNCA, GFI1B, CTSA, SNX13, RPA1, FLNA, XPNPEP1, KIF2A, ZBTB33, PSMD11, UBE2N, FOLR1, TSC22D1, PCNP, CELSR3, ACSBG1, RNF11, SEMA3E, MARCH2, PCDH24, SUPT5H, HLA-E, EGF, HLA-C, FLNA, CDK2AP1, LEPROT, SH3TC2, TUBA4A, MTMR1, TF, PRKD1, NAP1L1, DAB2, FUCA1, HIP1, THPO, MAP1B, PARVB, GP1BB, SEPT5, GJA4, PTGS1, GUCY1A3, HIST1H2AG, GNAS, LRBA, HYAL3, GP6, IGHG1, CYP2A13, CDC14B, MAX, KDM2A, CALD1, GNAZ, C19orf22, ARHGAP6, RHOC, RBX1, GP1BB, SEPT5, PRDX6, PRB4, FLNA, HIST1H2BF, RHBDF2, NUP205, SYT1, EGFL8, PPT2, TUBB1, TMC6, FLJ11292, NAP1L1, ALDH1A3, CSNK1E, PRUNE, COL4A3, ZNF221, ILF3, CABP5, RPA1, ARF1, HIST1H2BI, PTGS1, PRKAA1, GNB5, HIST2H4A, HIST2H4B, CYB5R3, TNS1, DCT, GMPR, ABI3BP, GNAS, SASH1, AAK1, XPO6, CTSL2, QSER1, MAP1LC3B, TBX6, CABP2, MRE11A, MAPRE2, TMC6, BDKRB2, MGLL, HRASLS, WHAMML1, WHAMML2, CLU, STC1, C6orf54, PABPN1, PDLIM1, CLU, PHF20, UBL4A, RNF115, HGD, RASGRP2, PNN, SAPS3, SFI1, GOLGA2, HIST2H2BE, SGEF, HGD, DUS1L, MPP1, HLA-E, GRB14, MMD, ZFHX4, CSNK1G2, HIST1H2BE, MPDZ, B2M, TBXA2R, CTDSPL, SNCA, CD99, POLS, MPL, HIST1H3F, SFRS8, NR5A2, ZMYM2, C6orf10, TMEM40, RNF43, PRUNE, MSH6, PLCB4, PARVB, TOX3, PKNOX1, RUFY1, SNCA, C10orf81, PDGFA, ASMT, HMGB1, CCDC90A, PROS1, hCG_1757335, RAP1B, MTSS1, GNRHR, LRRN3, MCM3AP, PLOD2, NAPIL1, PLOD2, HOXD13 CASKIN2, MFAP5, PITX2, SNCA, MYLK, PBX1, PRDX6, H3F3A, H3F3B, LOC440926, TMEM158, TRIM58, FSTL1, SNCA, TNS1, ATP1B1, C5orf4, LRP12, CTNNAL1, GEM, KIAA1466, ALDH1A2, MAP4K3, SNCA, RAB6B, PSD3, RIPK2, RAMP3, CALD1, CYP2E1, PSD3, PDLIM7, COBLL1, FUT3, SMOX, TGM2, LRRC50, CST6, OR7A17, C6orf145, DLEU2, DLEU2L, CPT2, HGF, TNS1, SPRY1, PLOD2, CD80, KYNU, BCAT1, NHLH1, AHCTF1, HOXA10, MTMR3, VAC14, CLCF1, FGF5, TAL1, SAMD14, ELL2, CHN1, SLC7A1, GRK5, PARD3, VPS37B, CYP2B6, CYP2B7P1, MALL, ALX4, SOX15, KRT5, ESPL1, STARD8, PSD3, KIAA0195, MYO9B, HIP1R, LOC100294412, EFNB1, ERN1, RHD, MFAP3L, PLA1A, POFUT2, C8orf39, CRYBB2, CYP4A11, PVRL2, CLCNKB, MRAS, NFIB, FKSG2, SLC11A2, FZR1, ZNF550, GLP1R, SLC19A1, RTN2, PAPOLA, STC1, GK, EXOSC6, RAPSN, HFE, EHD2, RIOK3, UBE2I, C15orf2, DMD, PRLH, MAP2K2, TP63, DACH1, PPP5C, SLC26A1, NUDT7, KCNJ12, ENTPD7, SLC26A1, PRRG3, RGS6, ZBED2, FICD, ARHGAP1, ARHGDIA, SDHB, AMHR2, ABCA4, TCF20, BGN, CASP7, LPAR4, GNA12, CYP2W1, RAX, C4A, C4B, LOC100292046, LOC100294156, PXN, ESR2, MYL10, EFS, TFF3, SRPK1, LOC441601, BIRC5, CCT8L2, PPAP2B, CMA1, APOA2, KDELR2, ASCL3, RUNX1, BUB1, SLC6A8, HNRNPC, HNRNPCL1, LOC440563, LOC649330, RIBC2, CLIC4, RAB17, SCML2, SPINLW1, ANK1, EDA2R, HTR4, CDC42EP4, KANK2, ANK1, SYN1, DUX3, DUX4, FRG2C, HPX-2, LOC100134409, LOC652119, LOC653543, LOC653544, LOC653545, LOC728410, PKNOX2, MLLT4, APOA2, PENK, GNAT1, FURIN, SEMA6A, EGFL6, HRH1, TSPAN1, DBC1, TRPC7, GPR52, HAMP, PRSS2, GPR107, FLJ11292, FLJ20184, B4GALT1, NKX3-1, ASIP, EFCAB6, GPR20, CA5A, PLK4, TAAR5, SRPX2, CNTD2, AZGP1, TIMP3, RGS6, ADARB11, DYNC1I1, C10orf10, PDIA2, PITX3, HOXC13, LPAR3, CTRC, CTSL2, MUC8, AQP5, UGT1A1, UGT1A10, UGT1A4, UGT1A6, UGT1A8, UGT1A9, KCNQ2, CYP2A13, ZNF155, KIAA0892, ATP2A2, FGF5, FGF18, FUT2, SHROOM2, PRSS3, CREB3L1, MGAT2, PLCE1, MLXIPL, OR10H3, ABCB11, CD84, ARHGEF4, ORC1L, PCIF1, CD177, C1orf116, IFT122, C11orf20, DUSP13, C6orf208, PLA2G5, PRAMEF1, PRAMEF2, CYP4F8, KCNA1, MFAP4, SLC4A3, IL1RAPL1, SERPINE1, ZCCHC14, POLR3G, C16orf8, FLJ14100, SMCHD1, ASCL1, FOXA2, SLC23A2, KLK13, MTSS1L, DNMT3L, RREB1, DNMBP, PKLR, C1orf106, CCDC134, MTSS1, CCDC40, HOXB1, SCNN1B, SEMA4G, RAPGEFL1, MAGEL2, PLSCR2, CHD2, PLCD1, C1orf116, CHRNA2, MBP, CDC42BPA, MYF6, PI15, LOC440895, SBF1, MAST1, GLT8D2, ERBB3, LOH3CR2A, AMH, HR, RDH8, PAWR, DRD3, CCT8, PRELP, SPOCK3, EPS8L3, NXN, SEMA4G3, P2RY1, AVL9, TEK, MOGAT2, KLK7, MT1E, MT1H, MT1M, CLDN18, RHBDF2, SIX1, INPP5A, KCNMB3, MAP2K5, GPD1, LPO, LOC729143, MPRIP, WNT7A, RARG, CDH7, MBNL2, RASGRP2, RBMY2FP, MASP1, CASR, EGR4, APOC2, HECW1, HOXB3, IRF5, NNMT, AOC2, ESRRG, LPIN1, ACOT11, CCDC33, MBD2, ZNF323, NTRK2, TMEM151B, GPLD1, LENEP, HNF1B, NXPH3, ALDH1A3, PHF20L1, CKM, PARD6B, CRYGB, HAB1, LARGE, RAB40C, MPL, CHIT1, METTL10, DUS4L, PNLIPRP1, ELL, ST8SIA5, GRIN2B, MC4R, RTDR1, HDAC6, KCNJ13, CPSF1, SPANXC, CNOT4, LAMA2, SLC1A6, ABCA2, KLK11, GFRA3, CYP3A4, SLC1A3, ATP2B2, APBB2, VPS45, GHRHR, HOXD4, PRPH, ADCY2, LEFTY2, CYP1B1, PCP4, C8B, RANBP3, PDE6H, TRIM15, VGLL1, TRIM3, CRKL, ADH7, PSG3, GPR153, MFAP2, FGF13, NAPA, ALDH3A1, MCM10, TLE4, ITPR3, CCDC87, C9orf7, ACTC1, OBSL1, MAP2, CRYM, RNF122, SST, HLA-DRB6, SLC22A17, HSPG2, HIP1, GRIK2, UNKL, GPR144, KIR3DX1, NARFL, UCP3, PLXNA2, BTN1A1, ERCC4, CIITA, EGFR, KRT33A, CLTB, B3GALT5, AP3M2, GJC1, MYO3A, ARHGAP1, PPP2R3A, CLIC4, C20orf19S, SIGLEC8, GPRC5A, CACNB1, MYL10, PRLR, OR2S2, NCR2, CHAF1B, EYA3, CDS1, FBXL18, ACTL6B, ZNF821, C16orf71, HBBP1, PLXNA1, CDC45L, MTCP1, PLCB4, PLVAP, PROX1, CYP3A43, IGHG1, RECQL5, IDUA, DLGAP4, PLXNB1, HSD17B14, FOXP3, C19orf26, EPB41L1, RBBP9, GJB4, UPK1B, CYP19A1, LOC55908, CLDN18, C2orf72, NTRK3, NRXN2, SPDEF, IGH@, IGHD, IGHG1, IGHM, LOC100289944, VSIG6, ACRV1, PHLDB1, SORBS1, HAPLN2, FABP3, EFS, ACVR1B, CHST3, UGT2A1, UGT2A2, TAF1, MT4, MFAP3, ETV5, UBQLN3, TBX10, GJB1, ABO, SPINK5, ATAD4, CDH11, CARD14, ALPP, ALPPL2, CBL, LRP4, CDKL2, SSX3, DSG2, SLC45A2, LAMA4, WFDC8, HTR7, EFNB3, TUBB2B, OR7E19P, PMS2L4, ASAP3, FRZB, PDLIM4, PVT1, TFR2, AHI1, TAF4, ADAMTSL2, CLDN4, KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL5A, KIR2DL5B, KIR2DS1, KIR2DS2, KIR2DS4, KIR2DS5, KIR3DL2, KIR3DL3, KIR3 DP1, LOC727787, RAPGEF5, CRMP1, LDB3, F11, USP46, IBSP, SLC9A3, FLRT3, TRIM17, FGF17, CAMK1G, GLYR1, CSH1, NTF3, ABHD6, TRIM15, OR52A1, FGFR2, ORAI2, C17orf53, GLP1R, SLIT1, TP63, DDR1, CFTR, DIO2, LETM1, ACSM5, ACTA1, NPR1, KCND3, POPDC3, DNAH3, SPDEF, CLEC4M, SLC30A3, NAGLU, AAK1, DHX34, NNAT, AKAP9, ICMT, FAM189A1, C10orf81, MYOZ1, PKNOX2, MGC31957, PRDM11, RET, IGHG1, XPNPEP2, NTRK2, SLC25A10, NR1I2, GRM8, OR3A3, GIPR, PAH, PACRG, CLN8, ZNF215, TRIO, TTLL5, GRM1, PRKG1, HHLA1, LAMA3, SLC37A4, HOXC11, SLCO5A1, CA10, RRBP1, SOD3, NTRK3, CYR61, STRA6, SLC6A11, CNOT4, ATN1, BCAP29, NOVA2, RELN, LAMC2, RAD51, PRSS7, DCBLD2, TACR2, RAB11B, OR2J2, VSNL1, IFNA17, DPYSL4, MGC2889, RRBP1, POLQ, OR1A2, PURA, AIF1, CBS, NECAB2, PRKCE, NOX1, IHH, EXO1, GPRIN2, PDX1, GPR12, FAM188A, HS3ST3B1, ASCL1, ZNF484, CSH1, BCAN, DDN, DUOX2, MORN1, SLC39A2, CLCN7, RUNX2, TTYH1, ZNF280B, PAX3, LZTS1, SLC8A2, HAB1, KIF1A, ARL4D, UGT2B15, NACA2, THRB, C6orf15, GPR176, WSCD1, PLXNB3, CADM3, HAP1, CYP1A2, SPAM1, IL22RA1, CDC2L5, IRX5, PPFIA2, KDELR3, CEACAM7, KCMF1, DUOX1, CDC27, HIST2H2AA3, CAV3, APOA4, NPR3, PRG3, TBC1D22B, TUSC3, RIMS2, CYP4F12, TBXA2R, HBEGF, PSG9, PYGO1, RASGRF1, SCN2A, KLHL1, DTNB, GREM1, SNCG, C22orf24, PALM, COBLL1, DNPEP, MNS1, NFATC4, DLC1, HSPC072, MCAM, CA12, CSHL1, RPA1N, COL5A2, UGT1A8, UGT1A9, IGH@, IGHA1, IGHG1, IGHG2, IGHG3, IGHM, LOC100126583, LOC100290036, LOC100290320, LOC100293211, LOC652494, ACSM5, ALOX12P2, ERBB4, CLDN16, CIB2, GALR3, MSMB, FABP7, ATXN3, KCNJ5, TRDN, CYP3A43, BAZ2A, ACCN4, SILV, DGCR14, SEMA6C, DIO2, PTHLH, LEP, PDZRN3, RGSL1, GJA4, SLC22A6, RASGRF1, MAPRE2, PVRL1, AKAP1, POMP, SOX21, DNAH9, HOXC5, SERHL2, KIAA0485, ITSN1, B4GALT1, NEK2, NUPR1, CCDC93, EPO, CRABP2, TYRO3, GOLGA2, SEMA3F, BFSP2, NCAM1, FOLH1, SSX2, TMPRSS4, DCN, LPHN3, POU4F3, CEACAM5, BCL3, EXTL3, CCNA1, DDR2, PAX8, SOX5, POU3F1, PEX16, NUP62, SIGLEC11, ALDOB, GPC3, IGFALS, WDR25, FGF1, OSR2, ARID1A, GYPA, KLK13, PARVB, LILRB5, RIMS2, C19orf21, HOXD1, PRSS3, FLT1, ATP6V1C1, LOX, CRYBB3, CA12, PRKG2, MASP1, LOC728395, LOC728403, TSPY1, PDCD1, GGTLC1, AQP8, KRT16, AICDA, BRD8, C1orf95, OR3A2, PFKFB2, FRZB, PAK3, MEIS2, ZSCAN2, MYH7, VWA1, LSAMP, SRC, UGT1A1, UGT1A10, UGT1A3, UGT1A4, UGT1A5, UGT1A6, UGT1A7, UGT1A8, UGT1A9, DIO1, TADA3L, NFASC, CALCRL, NBLA00301, MAB21L1, FBXO42, COL10A1, CFB, SNX7, FOXN1, SRY, HLF, CLCA3P, DAZ1, DAZ2, DAZ3, DAZ4, GPR3, TMPRSS11E, EMID1, KCNMB2, MUC5AC, SORT1, HIF3A, MAPK4, TCP11L1, ZZEF1, DCAF7, DMWD, CLCA2, VAC14, CSPG5, STMN2, MLLT4, GALNT14, FGF12, MFAP5, SUMO3, HTR3A, GDF5, TSSK1B, CYP2A7P1, MARK1, ATP1B2, TBX6, PAX8, IL1R1, RALYL, OR2B2, TAAR3, C12orf32, IGHG1, LOC642131, DICER1, GLRA3, PPARD, HSPA4L, WNT2, VIPR2, CYP2C9, SRPX2, IGSF1, ALPK3, TFPI, KCNS3, MARCH8, FRMD4B, TACR3, FIGF, PDCD6, TNN, SPANXB1, SPANXB2, SPANXF1, RHBDD3, SPP2, PDE10A, ZNF224, FGL1, PGAM2, CADM4, APOBEC2, SLC9A5, GNAT1, ARHGEF16, SMARCA2, DNAH9, RBM26, WNT2B, KCNK2, NPBWR2, SP2, TMPRSS11D, DENND2A, TNIP3, STC1, DOCK6, ADAM5P, SYDE1, TNPO2, LRTM1, USH1C, PDE12, SRCAP, OR10J1, OR2H2, KCNJ8, RP11-257K9.7, DOCK5, TPD52L1, PAEP, GGA2, PHLDA3, HES2, MLL, CHRNA6, CIB2, PTPRF, TM7SF4, DAZ1, DAZ2, DAZ3, DAZ4, ALX1, OR2F1, OR2F2, PLAT, HGC6.3, WNT11, PGK2, SNAI2, COL4A6, PRUNE2, ANKS1B, LOC81691, FERMT2, TIMP3, CST8, CAPN6, IDUA, GPR32, AKR1B10, GRHL2, FBXO24, HSF4, IGHG1, HCN2, LRP12, ARHGEF115, UGT1A1, UGT1A10, UGT1A7, UGT1A8, GUCA2A, ITIH1, EGFR, UGT1A1, UGT1A10, UGT1A3, UGT1A4, UGT1A5, UGT1A6, UGT1A7, UGT1A8, UGT1A9, MYOG, TMSB15A, TLX1, EDNRA, LOC100289791, MDFI, ZER1, MYH15, CDH20, GPR63, LOC440345, LOC440354, LOC595101, LOC641298, SMG1, HOXC10, KRTAP1-1, ARSD, CPLX3, LMAN1L, IFNA4, ABCC1, SEMA3E, MRE11A, C1QL1, LIPF, TRIM9, BBOX1, LRRC17, WNT2B, CYP3A4, SI, ANO3, OBSL1, CHRD, MSX2, PSG1, FAM107A, LRRC37B2, ANKLE2, PAX2, UNC5B, ADCYAP1R1, HFE, SYT1, GJC2, LOC100293871, FGF8, ACRV1, NRXN1, GDPD2, RGS4, CELA2A, IFNW1, MLNR, RNF17, LAD1, GLRA2, RASL12, MAGOH2, C6orf5S4, ZNF214, IKBKG, AP4E1, ZNRF4, OSBPL10, C1orf175, TTC4, PCDHB3, ADRBK1, ITSN1, XAGE1A, XAGE1B, XAGE1C, XAGE1D, XAGE1E, CDH22, FARP2, MYT1, TNC, MUC5AC, SLC6A15, PP14571, SMR3A, SMR3B, RXRG, SNX1, GLP1R, C6orf155, ATP1A2, TFAP4, PNPLA2, DIRAS3, ANO2, TACSTD2, MCM3AP, IL13RA2, TRIM10, RTEL1, PRRX2, TSHB, TIMELESS, FMO1, KIF18A, KIAA1199, CALB2, MFAP3L, PTGER3, EPAS1, SQSTM1, TSPY1, CPM, DLGAP1, CYP4F11, TLX3, PCDHA10, TAOK2, ERC1, TBX2, KALRN, DICER1, PAPPA, KIF5A, DNAJC22, OTUB1, KIAA1644, SEZ6L2, PCNXL2, HMHB1, ERG, SNTB2, GJA5, AGTR2, GJA3, GCK, LRRC61, CNTF, ZFP91, ZFP91-CNTF, PDLIM4, MPPED2, IFNA10, ACTN2, VGLL1, GJA9, LDLR, ANK2, COL1A1, TIMP3, OTOF, AGXT, GLI2, TRMT61A, FOXD2, TMEM212, DENND2A, B3GALT1, SPAG11A, PRDM4, TF, ELF5, GSC2, EPB41 L4B, GYG2, LYZL6, DCHS2, OBP2A, OBP2B, ANGPTL3, MYH11, NES, SLC17A1, RBM15B, CSH1, HTR5A, CYP3A7, HTR2A, KCNV2, TOX3, CLOCK, MAGEA6, FAM12A, COL4A3, S1PR2, NAT8, ACE2, SLC22A6, SLC13A2, MYH4, APBB2, RAP1GAP, SHOX2, SLCO1A2, ETV1, MAGEA12, PLA2G6, ADRA1A, SYT5, GPR161, SEMA3F, CYP3A43, HOMER2, KCNJ5, PPL, COL17A1, CSHL1, C9orf116, PARK2, UGT2B15, CDK6, FAM174B, CELA2A, CELA2B, SPDEF, EPB41, GAB1, SMR3A, PDE60, COL5A1, ABCA6, DMD, CYLC2, CIDEA, RAG2, HIST1H2BN, FMO6P, MAOA, ANKRD53, HAPLN1, MT1M, EHD2, GAD2, CRISP2, CSN2, SULT1C2, PCDHGA3, SSX3, FGFR2, GPR161, ATN1, CHD5, A4GALT, MYBPH, CSHL1, NCAPH2, CAPN9, CNGB1, BCAM, DRD5, NR5A2, TEF, ELAVL2, DGKB, HTR7P, RHAG, GH2, COL4A6, BMP7, SOSTDC1, SOX14, TAS2R9, LPHN2, MAP1A, OSGIN2, SLC10A2, FAM13C, EMX1, FLJ140330, CHI3L1, CDH16, SPRR1A, LOX, CALCB, GABBR2, CPB2, RASL11B, CCDC81, RUNX1, CPA1, CLCNKA, CLCNKB, FHL5, THSD7A, TFAP2C, SPAG11B, CAP2, PODNL1, SSX4, SSX4B, G6PC, RPE65, TMEM222, KDR, CHP2, GPR64, TPM2, TCEB3B, E2F5, IL5RA, AOC3, ABCF3, CPN2, ACE, NRP2, INPP5J, SMAD9, FAM155A, GART, PIR, ZNF467, ITSN2, NR1D1, THRA, RP11-35N6.1, LAMB1, EPHB3, PLA2R1, RAPGEF4, DNAJC8, ARSJ, TRIM49, GC, CDH2, ATXN3L, BTF3L1, BICC1, FAM186A, PTPRF, TRPC4, TCL6, CYP4A22, FUT6, MUC1, DKFZP434B2016, LOC643313, LDHA, LOC100131613, TRIM3, MLLT10, DZIP1, ANKRD34C, BUB1, CSPG5, FBLN1, GAD2, CLDN1, CHRNA3, SCN11A, TEX11, IL20RA, AKAP5, KBTBD10, MSTN, TLL2, NACAD, UNC93A, PTGER1, OLAH, NHLH2, SERPINA6, KRT17, KCNMA1, PRKCA, STS, LAMA1, GPR88, ACTN2, TREH, AKAP4, DKK4, PRICKLE3, IRS4, TRPV4, PCDH11Y, APBB2, SLCO2A1, DRD2, MTMR7, ZNF471, TF, NRIP2, ST6GALNAC5, COMT, PAH, LRRC19, PRKAR1B, HPR, PRDM5, NCRNA00120, LOC79999, ITSN2, CACNB2, GPR98, PREX2, FAM182B, LAMA4, ARVCF, HAS2, YOD1, PPP2R3A, COL4A1, RBM12B, GSTA3, FAM66D, OR10H2, PTHLH, ZNF674, KRT19, ACCN2, COL6A1, LOC100288442, LOC100289169, LOC728888, LOC729602, NPIPL2, NPIPL3, PDXDC2, SLC37A1, ATP6V1B1, ABI3BP, HR44, ZNF324B, ZNF584, HOXD13, ADH6, IFNA8, MYOZ2, NFATC4, ADAMTS7, FOXL1, GPR17, SLC18A3, MYH6, BOK, FGA, TEAD4, GRM1, EDNRA, C8orf79, METTL7A, FOLH1, RAD54L, SOX11, CNOT3, NTS, MAPK12, DOCK6, DNAJC6, HS3ST3A1, LOC728395, TSPY1, TSPY3, PTH, LAMB4, ALDOB, FLG, MLANA, UBE2D4, LOC100287483, KRT20, POU1F1, SLCO1B3, CLTA, MECOM, C8orf71, SULT2A1, C6orf1, SLC27A6, PRKD1, SYNPO2L, THPO, GABRR1, CFTR, PPP2R3A, DCBLD2, ANP32A, ANP32C, ANP32D, LOC723972, XYLT1, STAB1, STAB1, SASH1, PID1, FUCA1, SASH1, LRRN3, LRRN3 or a combination thereof.

In another embodiment, the gene is ITGB1/3/5, CXCL5/7, BMP6, ITGA2/8, ITGB1/3/4/5/6, ITGBL1, MMP16/24/26/28, ADAM12/18/22, IL-5/20/22, IL-9/36, TNFRSF11A/B, TGβ, LTBP4, MEK1/2, Smad2/3/4, PAI-1, SELP, ITFA8, ITGB1/3/5, CXCL5/7, BMP6, ITGA2/8, ITGB1/3/4/5/6, ITGBL1, MMP16/24/26/28, ADAM12/18/22, IL-5/13/20/22, IL-9/11/36, TNFRSF11A/B, TGβ, LTBP4, MEK1/2, Smad1/2/3/4/5/6/8, PAI-1, CCL19, IKKg, LTBP1 or a combination thereof. In another embodiment, the gene is SELP, ITFA8, ITGB1/3/5, CXCL5/7, BMP6, ITGA2/8, ITGB1/3/4/5/6, ITGBL1, MMP16/24/26/28, ADAM12/18/22, IL-1/1R/5/8/13/20/22, IL-9/11/12/36, TNFRSF11A/B, IFNA4/8/10/17, TGβ, LTBP4, MEK1/2, Smad1/2/3/4/5/6/8, PAI-1, CCL19, IKKg, LTBP1 or a combination thereof.

In one embodiment of any one of the methods, uses, pharmaceutical composition or packages described herein, the gene is TNFSF4, ITGB1/3/5, CXCL5/7, BMP6, ITGA2/8, ITGB1/3/4/5/6, ITGBL1, MMP16/24/26/28, ADAM12/18/22, IL-1/5/8/20/22, IL-9/12/36, TNFRSF11A/B, IFNA4/8/10/17, TGβ, LTBP4, MEK1/2, TGFβ type 1 receptor, Smad2/3/4, PAI-1, TNFSF4, SELP, ITFA8, ITGB1/3/5, CXCL5/7, a BMP6 gene, ITGA2/8, ITGβ1/3/4/5/6, ITGBL1, MMP16/24/26/28, ADAM12/18/22, IL-1/1R/5/8/13/20/22R, IL-9/11/12/36, TNFRSF11A/B, IFNA4/8/10/17, TGβ, LTBP4, MEK1/2, TGFβ type 1 receptor, type II BMPR, smad1/2/3/4/5/6/8, PAI-1, CCL19, IKKg, LTBP1, IL8R (CXCR1/2), Alpha tubulin, BMP2/4/7, MIS, TCF2, LFA-1, VLA-4, IL5R, IL13R, IL2OR, ITGB2, IFN gamma, TNF alpha, NKTR, TEF, CLSTN2, LUC7L2, FABP7, TPTE, FSTL1, SF3B1, LIMS1, PDE5A, XPNPEP1, C5orf4, SPANXB1, SPANXB2, SPANXF1, KRT20, TBC1D1, GRHL2, C5orf4, SEPT6, KIAA1199, SSX2IP, TPM1, CDC14B, USP47, MMRN1, CTNNAL1, SMOX, ALOX12, GLRA3, CA2, GUCY1B3, RFPL1, CLEC1B, GNG11, TSPAN32, RGS10, CALD1, PRKAR2B, CYP4F11, CLCA3P, CELSR3, CDC114B, TPM1, SEPT6, PRKG1, MAX, CCDC93, ARMCX6, LOC653354, TUBB2B, HIST1H2AJ, MFAP3L, LIMS1, GNB5, GPRASP1, SRRT, C1orf116, FBXO7, PPM1A, GUCY1B3, CTDSPL, GNAS, IGF2BP3, TPM1, HIST1H2BK, DLG4, WDR48, CALD1, LOC157627, GNB5, ZNF415, ASAP2, PSD3, GNAS, POPDC3, NRGN, ABLIM3, XYLT1, PTGIS, ARHGEF10, PDGFA, PGRMC1, HIST1H2AC, GNAS, CLDN5, MFAP3L, PGRMC1, MYST3, CAPRIN1, CALD1, FBXW7, DNM3, CD84, PRPF4B, RBM25, WASF3, GRAP2, SPARC, TAL1, NENF, XK, GP1BA, HLA-E, CA5A, LYVE1, MARCH6, NAT8B, TRIM58, RET. SDPR, TBXA2R, TMED10, APBA2, MYL9, POU1F1, H2BFS, HIST1H2BK, FAM12B, VCL, GSPT1, ALDOB, LOC150776, SMPD4, SLC37A1, SPARC, GNAS, TAS2R4, CALM3, POM121, POM121C, GRIK2, GREM1, TNNC2, EPS15L2, ENDOD1, RGS6, SF3B1, TMSB15A, ZBTB20, FUT9, ATP9A, MAX, HIST1H2AI, BAT2D1, ABL1, SNCA, GFI1B, CTSA, SNX13, RPA1, FLNA, XPNPEP1, KIF2A, ZBTB33, PSMD11, UBE2N, FOLR1, TSC22D1, PCNP, CELSR3, ACSBG1, RNF11, SEMA3E, MARCH2, PCDH24, SUPT5H, HLA-E, EGF, HLA-C, FLNA, CDK2AP1, LEPROT, SH3TC2, TUBA4A, MTMR1, TF, PRKD1, NAP1L1, DAB2, FUCA1, HIP1, THPO, MAP1B, PARVB, GP1BB, SEPT5, GJA4, PTGS1, GUCY1A3, HIST1H2AG, GNAS, LRBA, HYAL3, GP6, IGHG1, CYP2A13, CDC14B, MAX, KDM2A, CALD1, GNAZ, C19orf22, ARHGAP6, RHOC, RBX1, GP1BB, SEPT5, PRDX6, PRB4, FLNA, HIST1H2BF, RHBDF2, NUP205, SYT1, EGFL8, PPT2, TUBB1, TMC6, FLJ11292, NAP1L1, ALDH1A3, CSNK1E, PRUNE, COL4A3, ZNF221, ILF3, CABP5, RPA1, ARF1, HIST1H2BI, PTGS1, PRKAA1, GNB5, HIST2H4A, HIST2H4B, CYB5R3, TNS1, DCT, GMPR, ABI3BP, GNAS, SASH1, AAK1, XPO6, CTSL2, QSER1, MAP1LC3B, TBX6, CABP2, MRE11A, MAPRE2, TMC6, BDKRB2, MGLL, HRASLS, WHAMML1, WHAMML2, CLU, STC1, C6orf54, PABPN1, PDLIM1, CLU, PHF20, UBL4A, RNF115, HGD, RASGRP2, PNN, SAPS3, SFI1, GOLGA2, HIST2H2BE, SGEF, HGD, DUS1L, MPP1, HLA-E, GRB14, MMD, ZFHX4, CSNK1G2, HIST1H2BE, MPDZ, B2M, TBXA2R, NGFRAP1, CTDSPL, SNCA, CD99, POLS, MPL, HIST1H3F, SFRS8, NR5A2, ZMYM2, C6orf10, TMEM40, RNF43, PRUNE, MSH6, PLCB4, PARVB, TOX3, PKNOX1, RUFY1, SNCA, C10orf81, PDGFA, ASMT, HMGB1, CCDC90A, PROS1, hCG_1757335, RAP1B, MTSS1, GNRHR, LRRN3, MCM3AP, PLOD2, NAP1L1, PLOD2, HOXD13 CASKIN2, MFAP5, PITX2, SNCA, MYLK, PBX1, PRDX6, EIF2AK1, H3F3A, H3F3B, LOC440926, TMEM158, TRIM58, FSTL1, SNCA, TNS1, ATP1B1, C5orf4, LRP12, CTNNAL1, GEM, KIAA1466, ALDH1A2, MAP4K3, SNCA, RAB6B, PSD3, RIPK2, RAMP3, CALD1, CYP2E1, PSD3, PDLIM7, COBLL1, FUT3, SMOX, TGM2, LRRC50, CST6, OR7A17, C6orf145, DLEU2, DLEU2L, CPT2, HGF, TNS1, SPRY1, PLOD2, CD80, KYNU, BCAT1, NHLH1, AHCTF1, HOXA10, MTMR3, VAC14, CLCF1, FGF5, TAL1, SAMD14, ELL2, CHN1, SLC7A1, GRK5, PARD3, VPS37B, CYP2B6, CYP2B7P1, MALL, ALX4, SOX15, KRT5, ESPL1, STARD8, PSD3, KIAA0195, MYO9B, HIP1R, LOC100294412, EFNB1, ERN1, RHD, MFAP3L, PLA1A, POFUT2, C8orf39, CRYBB2, CYP4A11, PVRL2, CLCNKB, MRAS, NFIB, FKSG2, SLC11A2, FZR1, ZNF550, GLP1R, SLC19A1, RTN2, PAPOLA, STC1, GK, EXOSC6, RAPSN, HFE, EHD2, RIOK3, UBE2I, C15orf2, DMD, PRLH, MAP2K2, TP63, DACH1, PPP5C, SLC26A1, NUDT7, KCNJ12, ENTPD7, SLC26A1, PRRG3, RGS6, ZBED2, FICD, ARHGAP1, ARHGDIA, SDHB, AMHR2, ABCA4, TCF20, BGN, CASP7, LPAR4, GNA12, CYP2W1, RAX, C4A, C4B, LOC100292046, LOC100294156, ELAVL4, PXN, ESR2, MYL10, EFS, TFF3, SRPK1, LOC441601, BIRC5, CCT8L2, PPAP2B, CMA1, APOA2, KDELR2, ASCL3, RUNX1, BUB1, SLC6A8, HNRNPC, HNRNPCL1, LOC440563, LOC649330, RIBC2, CLIC4, RAB17, SCML2, SPINLW1, ANK1, EDA2R, HTR4, CDC42EP4, KANK2, ANK1, SYN1, DUX3, DUX4, FRG2C, HPX-2, LOC100134409, LOC652119, LOC653543, LOC653544, LOC653545, LOC728410, PKNOX2, MLLT4, APOA2, PENK, GNAT1, FURIN, SEMA6A, EGFL6, HRH1, TSPAN1, DBC1, TRPC7, MDM2, GPR52, HAMP, PRSS2, GPR107, FLJ11292, FLJ20184, B40ALT1, NKX3-1, ASIP, EFCAB6, GPR20, CA5A, PLK4, TAAR5, SRPX2, CNTD2, AZGP1, TIMP3, RGS6, ADARB1, DYNC1I1, C10orf10, PDIA2, PITX3, HOXC13, LPAR3, CTRC, CTSL2, MUC8, AQP5, UGT1A1, UGT1A10, UGT1A4, UGT1A6, UGT1A8, UGT1A9, KCNQ2, CYP2A13, ZNF155, KIAA0892, ATP2A2, FGF5, FGF18, FUT2, SHROOM2, PRSS3, CREB3L1, MGAT2, PLCE1, MLXIPL, OR10H3, ABCB11, CD84, ARHGEF4, ORC1L, PCIF1, CD177, C1orf116, IFT122, C11orf20, DUSP13, C6orf208, PLA2G5, PRAMEF1, PRAMEF2, CYP4F8, KCNA1, MFAP4, C6, SLC4A3, IL1RAPL1, SERPINE1, ZCCHC14, POLR3G, C16orf8, FLJ14100, SMCHD1, ASCL1, FOXA2, SLC23A2, KLK13, MTSS1L, DNMT3L, RREB1, DNMBP, PKLR, C1orf106, CCDC134, MTSS1, CCDC40, HOXB1, SCNN1B, SEMA4G, RAPGEFL1, MAGEL2, PLSCR2, CHD2, PLCD1, C1orf116, CHRNA2, MBP, CDC42BPA, MYF6, PI15, LOC440895, SBF1, MAST1, GLT8D2, ERBB3, LOH3CR2A, AMH, HR, RDH8, PAWR, DRD3, CCT8, PRELP, SPOCK3, EPS8L3, NXN, SEMA4G, P2RY1, AVL9, TEK, MOGAT2, KLK7, MT1E, MT1H, MT1M, CLDN18, RHBDF2, SIX1, INPP5A, KCNMB3, MAP2K5, GPD1, LPO, LOC729143, MPRIP, WNT7A, RARG, CDH7, MBNL2, RASGRP2, RBMY2FP, MASP1, CASR, EGR4, APOC2, HECW1, HOXB3, IRF5, NNMT, AOC2, ESRRG, LPIN1, ACOT11, CCDC33, MBD2, ZNF323, NTRK2, TMEM151B, GPLD1, LENEP, HNF1B, NXPH3, ALDH1A3, PHF20L1, CKM, PARD6B, CRYGB, HAB1, LARGE, RAB40C, MPL, CHIT1, METTL10, DUS4L, PNLIPRP1, ELL, ST8SIA5, GRIN2B, MC4R, RTDR1, HDAC6, KCNJ13, CPSF1, SPANXC, CNOT4, LAMA2, SLC1A6, ABCA2, KLK11, GFRA3, CYP3A4, SLC1A3, ATP2B2, APBB2, VPS45, GHRHR, HOXD4, PRPH, ADCY2, LEFTY2, CYP1B1, PCP4, C8B, RANBP3, PDE6H, TRIM15, VGLL1, TRIM3, CRKL, ADH7, PSG3, GPR153, MFAP2, FGF13, NAPA, ALDH3A1, MCM10, TLE4, ITPR3, CCDC87, C9orf7, ACTC1, OBSL1, MAP2, CRYM, RNF122, SST, HLA-DRB6, SLC22A17, HSPG2, HIP1, GRIK2, UNKL, GPR144, KIR3DX1, NARFL, UCP3, PLXNA2, BTN1A1, ERCC4, CIITA, EGFR, KRT33A, CLTB, B3GALT5, AP3M2, GJC1, MYO3A, ARHGAP1, PPP2R3A, CLIC4, C20orf195, SIGLEC8, GPRC5A, CACNB1, MYL10, PRLR, OR2S2, NCR2, CHAF1B, EYA3, CDS1, FBXL18, ACTL6B, ZNF821, C16orf71, HBBP1, PLXNA1, CDC45L, MTCP1, PLCB4, PLVAP, PROX1, CYP3A43, IGHG1, RECQL5, IDUA, DLGAP4, PLXNB1, HSD17B14, FOXP3, C19orf26, EPB41L1, RBBP9, GJB4, UPK1B, CYP19A1, LOC55908, CLDN18, C2orf72, NTRK3. NRXN2, SPDEF, IGH@IGHD, IGHG1, IGHM, LOC100289944, VSIG6, ACRV1, PHLDB1, SORBS1, HAPLN2, FABP3, EFS, ACVR1B, CHST3, UGT2A1, UGT2A2, TAF1, MT4, MFAP3, ETV5, UBQLN3, TBX10, GJB1, ABO, SPINK5, ATAD4, CDH11, CARD14, ALPP, ALPPL2, CBL, LRP4, CDKL2, SSX3, DSG2, SLC45A2, LAMA4, WFDC8, HTR7, EFNB3, TUBB2B, OR7E19P, PMS2L4, ASAP3, FRZB, PDLIM4, PVT1, TFR2, AHI1, TAF4, ADAMTSL2, CLDN4, KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL5A, KIR2DL5B, KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS4, KIR2DS5, KIR3DL2, KIR3DL3, KIR3 DP1, LOC727787, RAPGEF5, CRMP1, LDB3, F11, USP46, PTN, IBSP, SLC9A3, FLRT3, TRIM17, FGF17, CAMK1G, GLYR1, CSH1, NTF3, ABHD6, TRIM15, OR52A1, FGFR2, ORAI2, C17orf53, GLP1R, SLIT1, TP63, DDR1, CFTR, DIO2, LETM1, ACSM5, ACTA1, NPR1, KCND3, POPDC3, DNAH3, SPDEF, CLEC4M, SLC30A3, NAGLU, AAK1, DHX34, NNAT, AKAP9, ICMT, FAM189A1, C10orf81, MYOZ1, PKNOX2, MGC31957, PRDM11, RET, IGHG1, XPNPEP2, NTRK2, SLC25A10, NR1I2, GRM8, OR3A3, GIPR, PAH, PACRG, CLN8, ZNF215, TRIO, TTLL5, GRM1, PRKG1, HHLA1, LAMA3, PTN, SLC37A4, HOXC11, SLCO5A1, CA10, RRBP1, SOD3, NTRK3, CYR61, STRA6, SLC6A11, CNOT4, ATN1, BCAP29, NOVA2, RELN, LAMC2, RAD51, PRSS7, DCBLD2, TACR2, RAB11B, OR2J2, VSNL1, IFNA17, DPYSL4, MGC2889, RRBP1, POLQ, OR1A2, PURA, AIF1, CBS, NECAB2, PRKCE, NOX1, IHH, EXO1, GPRIN2, PDX1, GPR12, FAM188A, HS3ST3B1, ASCL1, ZNF484, CSH1, BCAN, DDN, DUOX2, MORN11, SLC39A2, CLCN7, RUNX2, TTYH1, ZNF280B, PAX3, LZTS1, SLC8A2, HAB1, KIF1A, ARL4D, UGT2B15, NACA2, THRB, C6orf15, GPR176, WSCD1, PLXNB3, CADM3, HAP1, CYP1A2, SPAM1, IL22RA1, CDC2L5, IRX5, PPFIA2, KDELR3, CEACAM7, KCMF1, DUOX1, CDC27, HIST2H2AA3, CAV3, APOA4, NPR3, PRG3, TBC1D22B, TUSC3, RIMS2, CYP4F12, TBXA2R, HBEGF, PSG9, PYGO1, RASGRF1, SCN2A, KLHL1, DTNB, GREM1, SNCG, C22orf24, PALM, COBLL1, DNPEP, MNS1, NFATC4, DLC1, HSPC072, MCAM, CA12, CSHL1, RPAIN, COL5A2, UGT1A8, UGT1A9, IGH@, IGHA1, IGHG1, IGHG2, IGHG3, IGHM, LOC100126583, LOC100290036, LOC100290320, LOC100293211, LOC652494, TGFB2, ACSM5, ALOX12P2, ERBB4, CLDN16, CIB2, GALR3, MSMB, FABP7, ATXN3, KCNJ5, TRDN, CYP3A43, BAZ2A, ACCN4, SILV, DGCR14, SEMA6C, DIO2, PTHLH, LEP, PDZRN3, RGSL1, GJA4, SLC22A6, RASGRF1, MAPRE2, PVRL1, AKAP1, POMP, SOX21, DNAH9, HOXC5, SERHL2, KIAA0485, ITSN1, B4GALT1, NEK2, NUPR1, CCDC93, EPO, CRABP2, TYRO3, GOLGA2, SEMA3F, BFSP2, NCAM1, FOLH1, SSX2, TMPRSS4, DCN, LPHN3, POU4F3, CEACAM5, BCL3, EXTL3, CCNA1, DDR2, PAX8, SOX5, POU3F1, PEX16, IL4I1, NUP62, SIGLEC11, ALDOB, GPC3, IGFALS, WDR25, FGF1, OSR2, ARID1A, GYPA, KLK13, PARVB, LILRB5, RIMS2, C19orf21, HOXD1, PRSS3, FLT1, ATP6V1C1, LOX, CRYBB3, CA12, PRKG2, MASP1, LOC728395, LOC728403, TSPY1, PDCD1, GGTLC1, AQP8, IL1F9, KRT16, AICDA, BRD8, C1orf95, OR3A2, PFKFB2, FRZB, PAK3, MEIS2, ZSCAN2, MYH7, VWA1, LSAMP, SRC, UGT1A1, UGT1A10, UGT1A3, UGT1A4, UGT1A5, UGT1A6, UGT1A7, UGT1A8, UGT1A9, DIO1, TADA3L, NFASC, CALCRL, NBLA00301, MAB21L1, FBXO42, COL10A1, CFB, SNX7, FOXN1, SRY, HLF, CLCA3P, DAZ1, DAZ2, DAZ3, DAZ4, GPR3, TMPRSS11E, EMID1, KCNMB2, MUC5AC, SORT1, HIF3A, MAPK4, TCP11L1, ZZEF1, DCAF7, DMWD, CLCA2, VAC14, CSPG5, STMN2, MLLT4, GALNT14, FGF12, MFAP5, SUMO3, HTR3A, GDF5, TSSK1B, CYP2A7P1, MARK1, ATP1B2, TBX6, PAX8, IL1R1, RALYL, OR2B2, TAAR3, C12orf32, IGHG1, LOC642131, DICER1, GLRA3, PPARD, HSPA4L, WNT2, VIPR2, CYP2C9, SRPX2, IGSF1, ALPK3, TFPI, KCNS3, MARCH8, FRMD4B, TACR3, FIGF, PDCD6, TNN, SPANXB1, SPANXB2, SPANXF1, RHBDD3, SPP2, PDE10A, ZNF224, FGL1, PGAM2, CADM4, APOBEC2, SLC9A5, GNAT1, ARHGEF16, SMARCA2, DNAH9, RBM26, WNT2B, KCNK2, NPBWR2, SP2, TMPRSS11D, DENND2A, TNIP3, STC1, DOCK6, ADAM5P, SYDE1, TNPO2, LRTM1, USH1C, PDE12, SRCAP, OR10J1, OR2H2, KCNJ8, RP11-257K9.7, DOCK5, TPD52L1, PAEP, GGA2, PHLDA3, HES2, MLL, PTN, CHRNA6, CIB2, PTPRF, TM7SF4, DAZ1, DAZ2, DAZ3, DAZ4, ALX1, OR2F1, OR2F2, PLAT, HGC6.3, WNT11, PGK2, SNAI2, COL4A6, PRUNE2, ANKS1B, LOC81691, FERMT2, TIMP3, CST8, CAPN6, IDUA, GPR32, AKR1B10, GRHL2, FBXO24, HSF4, IGHG1, HCN2, LRP12, ARHGEF15, UGT1A1, UGT1A10, UGT1A7, UGT1A8, GUCA2A, MDK, ITIH1, EGFR, UGT1A1, UGT1A10, UGT1A3, UGT1A4, UGT1A5, UGT1A6, UGT1A7, UGT1A8, UGT1A9, MYOG, TMSB15A, TLX1, EDNRA, LOC100289791, MDFI, ZER1, MYH15, CDH20, GPR63, LOC440345, LOC440354, LOC595101, LOC641298, SMG1, HOXC10, KRTAP1-1, ARSD, CPLX3, LMAN1L, IFNA4, ABCC1, SEMA3E, MRE11A, C1QL1, LIPF, TRIM9, BBOX1, LRRC17, WNT2B, CYP3A4, SI, ANO3, OBSL1, CHRD, MSX2, PSG1, FAM107A, LRRC37B2, ANKLE2, PAX2, UNC5B, ADCYAP1R1, HFE, SYT1, GJC2, LOC100293871, FGF8, ACRV1, NRXN1, GDPD2, RGS4, CELA2A, IFNW1, MLNR, RNF17, LAD1, GLRA2, RASL12, MAGOH2, C6orf54, ZNF214, IKBKG, AP4E1, ZNRF4, OSBPL10, C1orf175, TTC4, PCDHB3, ADRBK1, ITSN1, XAGE1A, XAGE1B, XAGE1C, XAGE1D, XAGE1E, CDH22, FARP2, MYT1, TNC, MUC5AC, SLC6A15, PP14571, SMR3A, SMR3B, RXRG, SNX1, GLP1R, C6orf155, ATP1A2, TFAP4, PNPLA2, DIRAS3, ANO2, TACSTD2, MCM3AP, IL13RA2, TRIM10, RTEL1, PRRX2, TSHB, TIMELESS, FMO1, KIF18A, KIAA1199, CALB2, MFAP3L, PTGER3, EPAS1, SQSTM1, TSPY1, CPM, DLGAP1, CYP4F11, TLX3, PCDHA10, TAOK2, ERC1, TBX2, KALRN, DICER1, PAPPA, KIF5A, DNAJC22, OTUB1, KIAA1644, SEZ6L2, PCNXL2, HMHB1, ERG, SNTB2, GJA5, AGTR2, GJA3, GCK, LRRC61, CNTF, ZFP91, ZFP91-CNTF, PDLIM4, MPPED2, IFNA10, ACTN2, VGLL1, GJA9, LDLR, ANK2, COL1A1, TIMP3, OTOF, AGXT, GLI2, TRMT61A, FOXD2, TMEM2I2, DENND2A, B3GALT1, SPAG11A, PRDM4, TF, ELF5, GSC2, EPB41L4B, GYG2, LYZL6, DCHS2, OBP2A, OBP2B, ANGPTL3, MYH11, NES, SLC17A1, RBM15B, CSH1, HTR5A, CYP3A7, HTR2A, KCNV2, TOX3, CLOCK, MAGEA6, FAM12A, COL4A3, S1PR2, NAT8, ACE2, SLC22A6, SLC13A2, MYH4, APBB2, RAP1GAP, SHOX2, SLCO1A2, ETV1, MAGEA12, PLA2G6, ADRA1A, SYT5, GPR161, SEMA3F, CYP3A43, HOMER2, KCNJ5, PPL, COL17A1, CSHL1, C9orf116, PARK2, UGT2B15, CDK6, FAM174B, CELA2A, CELA2B, SPDEF, EPB41, GAB1, SMR3A, PDE6G, COL5A1, ABCA6, DMD, CYLC2, CIDEA, RAG2, HIST1H2BN, FMO6P, MAOA, ANKRD53, HAPLN1, MT1M, EHD2, GAD2, CRISP2, CSN2, SULT1C2, PCDHGA3, SSX3, FGFR2, GPR161, ATN1, CHD5, A4GALT, MYBPH, CSHL1, NCAPH2, CAPN9, CNGB1, BCAM, DRD5, NR5A2, TEF, ELAVL2, DGKB, HTR7P, RHAG, GH2, COL4A6, BMP7, SOSTDC1, SOX14, TAS2R9, LPHN2, MAP1A, OSGIN2, SLC10A2, FAM13C, EMX1, FLJ40330, CHI3L1, CDH16, SPRR1A, LOX, CALCB, GABBR2, CPB2, RASL11B, CCDC81, RUNX1, CPA1, CLCNKA, CLCNKB, FHL5, THSD7A, TFAP2C, SPAG11B, CAP2, PODNL1, SSX4, SSX4B, G6PC, RPE65, TMEM222, KDR, CHP2, GPR64, TPM2, TCEB3B, E2F5, IL5RA, AOC3, ABCF3, CPN2, ACE, NRP2, INPP5J, SMAD9, FAM155A, GART, PIR, ZNF467, ITSN2, NRID1, THRA, RP11-35N6.1, LAMB1, EPHB3, PLA2R1, RAPGEF4, DNAJC8, ARSJ, TRIM49, GC, IL12B, CDH2, ATXN3L, BTF3L1, BICC1, FAM186A, PTPRF, TRPC4, TCL6, CYP4A22, FUT6, MUC1, DKFZP434B2016, LOC643313, LDHA, LOC100131613, TRIM3, MLLT10, DZIP1, ANKRD34C, BUB1, CSPG5. FBLN1, GAD2, CLDN1, CHRNA3, SCN11A, TEX11, IL20RA, AKAP5, KBTBD10, MSTN, TLL2, NACAD, UNC93A, PTGER1, OLAH, NHLH2, SERPINA6, KRT17, KCNMA1, PRKCA, STS, LAMA1, GPR88, ACTN2, TREH, AKAP4, DKK4, PRICKLE3, IRS4, TRPV4, PCDH11Y, APBB2, SLCO2A1, DRD2, MTMR7, ZNF471, TF, NRIP2, ST6GALNAC5, COMT, PAH, LRRC19, PRKAR1B, HPR, PRDM5, NCRNA00120, LOC79999, ITSN2, CACNB2, GPR98, PREX2, FAM182B, LAMA4, ARVCF, HAS2, YOD1, PPP2R3A, COL4A1, RBM12B, GSTA3, FAM66D, OR10H2, PTHLH, ZNF674, KRT19, ACCN2, COL6A1, LOC100288442, LOC100289169, LOC728888, LOC729602, NPIPL2, NPIPL3, PDXDC2, SLC37A1, ATP6V1B1, PTN, ABI3BP, HR44, ZNF324B, ZNF584, HOXD13, ADH6, IFNA8, MYOZ2, NFATC4, ADAMTS7, FOXL1, GPR17, SLC18A3, MYH6, BOK, FGA, TEAD4, GRM1, EDNRA, C8orf79, METTL7A, FOLH1, RAD54L, SOX11, CNOT3, NTS, MAPK12, DOCK6, DNAJC6, HS3ST3A1, LOC728395, TSPY1, TSPY3, PTH, LAMB4, ALDOB, FLG, MLANA, UBE2D4, LOC100287483, KRT20, POU1F1, SLCO1B3, CLTA, MECOM, C8orf71, SULT2A1, C6orf10, SLC27A6, PRKD1, SYNPO2L, THPO, GABRR1, CFTR, PPP2R3A, DCBLD2, ANP32A, ANP32C, ANP32D, LOC723972, XYLT1, STAB1, STAB1, SASH1, PID1, FUCA1, SASH1, LRRN3, LRRN3 or any combination thereof.

In another embodiment, the gene is TNFSF4, ITGB1/3/5, CXCL5/7, BMP6, ITGA2/8, ITGβB/3/4/5/6, ITGBL1, MMP16/24/26/28, ADAM12/18/22, IL-1/5/8/20/22, IL-9/12/36, TNFRSF11A/B, IFNA4/8/10/17, TGβ, LTBP4, MEK1/2, TGFβ type 1 receptor, Smad2/3/4, PAI-1, TNFSF4, SELP, ITFA8, ITGB1/3/5, CXCL5/7, a BMP6 gene, ITGA2/8, ITGβ1/3/4/5/6, ITGBL1, MMP16/24/26/28, ADAM12/18/22, IL-1/1R/5/8/13/20/22R, IL-9/11/12/36, TNFRSF11A/B, IFNA4/8/10/17, TGβ, LTBP4, MEK1/2, TGFβ type 1 receptor, type 11 BMPR, smad1/2/3/4/5/6/8, PAI-1, CCL19, IKKg, LTBP1 or any combination thereof. In yet another embodiment, the gene is TNFSF4, ITGB1/3/5, CXCL5/7, BMP6, ITGA2/8, ITGB1/3/4/5/6, ITGBL1, MMP16/24/26/28, ADAM12/18/22, IL-1/5/8/20/22, IL-9/12/36, TNFRSF11A/B, IFNA4/8/10/17, TGβ, LTBP4, MEK1/2, TGFβ type 1 receptor, Smad2/3/4, PAI-1 or any combination thereof.

In one embodiment, laquinimod is administered orally. In another embodiment, laquinimod is administered daily.

In one embodiment, laquinimod is administered at a dose of less than 0.6 mg/day. In another embodiment, laquinimod is administered at a dose of 0.1-40.0 mg/day. In another embodiment, laquinimod is administered at a dose of 0.1-2.5 mg/day. In another embodiment, laquinimod is administered at a dose of 0.25-2.0 mg/day. In another embodiment, laquinimod is administered at a dose of 0.5-1.2 mg/day. In another embodiment, laquinimod is administered at a dose of 0.25 mg/day. In another embodiment, laquinimod is administered at a dose of 0.3 mg/day. In another embodiment, laquinimod is administered at a dose of 0.5 mg/day. In another embodiment, laquinimod is administered at a dose of 0.6 mg/day. In another embodiment, laquinimod is administered at a dose of 1.0 mg/day. In another embodiment, laquinimod is administered at a dose of 1.2 mg/day. In another embodiment, laquinimod is administered at a dose of 1.5 mg/day. In yet another embodiment, laquinimod is administered at a dose of 2.0 mg/day.

In one embodiment, the subject is a naïve subject. In another embodiment, the subject is naïve to laquinimod. In another embodiment, the subject has been previously administered laquinimod.

In another embodiment, the subject has been previously administered a multiple sclerosis drug other than laquinimod.

In an embodiment, the step of evaluating expression of the biomarker comprises normalization of the subject's gene expression. In another embodiment, the step of evaluating expression of the biomarker comprises comparing expression level in the subject relative to a reference value. In another embodiment, the reference value is based on the level of expression of the biomarker in a laquinimod Non-Responder population. In another embodiment, the reference value is based on the level of expression of the biomarker in a healthy control population. In yet another embodiment, the reference value is based on the level of expression of the subject at baseline.

In one embodiment, the subject is identified as a laquinimod responder if expression of the biomarker is higher than a reference value. In yet another embodiment, the subject is identified as a laquinimod responder if expression level of the biomarker is lower than a reference value.

In one embodiment, expression of the biomarker is evaluated in the blood of the subject. In another embodiment, expression of the biomarker is evaluated in the peripheral blood mononuclear cells (PBMCs) of the subject. In another embodiment, expression of the biomarker is evaluated prior to treatment with laquinimod.

In one embodiment, expression of the biomarker is evaluated after beginning treatment with laquinimod. In another embodiment, expression of the biomarker is evaluated one month after beginning treatment with laquinimod. In another embodiment, expression of the biomarker is evaluated 6 months after beginning treatment with laquinimod. In another embodiment, expression of the biomarker is evaluated 12 months after beginning treatment with laquinimod. In another embodiment, expression of the biomarker is evaluated 24 months after beginning treatment with laquinimod.

In one embodiment, if the subject is identified as a laquinimod responder, the subject is thereafter administered a pharmaceutical composition comprising laquinimod and a pharmaceutically acceptable carrier as monotherapy. In another embodiment, if the subject is identified as a laquinimod responder, the subject is thereafter administered a pharmaceutical composition comprising laquinimod and a pharmaceutically acceptable carrier in combination with another multiple sclerosis drug. In another embodiment, if the subject is identified as a laquinimod non-responder, the subject is thereafter administered a multiple sclerosis drug which is not laquinimod.

In one embodiment, the subject is a human patient.

The subject invention also provides laquinimod for use in treating a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome, wherein the subject has been identified as a laquinimod responder.

The subject invention also provides a pharmaceutical composition comprising an amount of laquinimod for use in treating a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome, wherein the subject has been identified as a laquinimod responder

The subject invention also provides laquinimod for use in treating a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome, wherein expression of a biomarker in the subject is up-regulated and the biomarker is a gene associated with inflammatory response, a gene associated with cellular movement, a gene associated with cell signaling, a gene associated with cell development, a gene associated with hematological system, or a combination thereof.

The subject invention also provides a pharmaceutical composition comprising an amount of laquinimod for use in treating a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome, wherein expression of a biomarker in the subject is up-regulated and the biomarker is a gene associated with inflammatory response, a gene associated with cellular movement, a gene associated with cell signaling, a gene associated with cell development, a gene associated with hematological system, or a combination thereof.

The subject invention also provides laquinimod for use in treating a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome, wherein expression of a biomarker in the subject is suppressed and the biomarker is a gene associated with inflammatory response, a gene associated with cellular movement, a gene associated with cell signaling, a gene associated with cell development, a gene associated with hematological system, or a combination thereof.

The subject invention also provides a pharmaceutical composition comprising an amount of laquinimod for use in treating a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome, wherein expression of a biomarker in the subject is suppressed and the biomarker is a gene associated with inflammatory response, a gene associated with cellular movement, a gene associated with cell signaling, a gene associated with cell development, a gene associated with hematological system, or a combination thereof.

The subject invention also provides a therapeutic package for dispensing to, or for use in dispensing to, a subject identified as a laquinimod responder afflicted with multiple sclerosis or presenting a clinically isolated syndrome, which comprises: a) one or more unit doses, each such unit dose comprising an amount of laquinimod, and b) a finished pharmaceutical container therefor, said container containing said unit dose or unit doses, said container further containing or comprising labeling directing the use of said package in the treatment of said subject.

The subject invention also provides a therapeutic package for dispensing to, or for use in dispensing to, a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome, which comprises: a) one or more unit doses, each such unit dose comprising an amount of laquinimod, and b) a finished pharmaceutical container therefor, said container containing said unit dose or unit doses, said container further containing or comprising labeling directing the use of said package in the treatment of said subject, wherein expression of a biomarker in the subject is suppressed or up-regulated and the biomarker is a gene associated with inflammatory response, a gene associated with cellular movement, a gene associated with cell signaling, a gene associated with cell development, a gene associated with hematological system, or a combination thereof.

For the foregoing embodiments, each embodiment disclosed herein is contemplated as being applicable to each of the other disclosed embodiment. For example, the elements recited in the method embodiments can be used in the use and package embodiments described herein and vice versa.

A pharmaceutically acceptable salt of laquinimod as used in this application includes lithium, sodium, potassium, magnesium, calcium, manganese, copper, zinc, aluminum and iron. Salt formulations of laquinimod and the process for preparing the same are described, e.g., in U.S. Patent Application Publication No. 2005/0192315 and PCT International Application Publication No. WO 2005/074899, which are hereby incorporated by reference into this application.

A dosage unit may comprise a single compound or mixtures of compounds thereof. A dosage unit can be prepared for oral dosage forms, such as tablets, capsules, pills, powders, and granules.

Laquinimod can be administered in admixture with suitable pharmaceutical diluents, extenders, excipients, or carriers (collectively referred to herein as a pharmaceutically acceptable carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices. The unit will be in a form suitable for oral administration. Laquinimod can be administered alone but is generally mixed with a pharmaceutically acceptable carrier, and co-administered in the form of a tablet or capsule, liposome, or as an agglomerated powder. Examples of suitable solid carriers include lactose, sucrose, gelatin and agar. Capsule or tablets can be easily formulated and can be made easy to swallow or chew; other solid forms include granules, and bulk powders. Tablets may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents flow-inducing agents, and melting agents.

Specific examples of the techniques, pharmaceutically acceptable carriers and excipients that may be used to formulate oral dosage forms of the present invention are described, e.g., in U.S. Patent Application Publication No. 2005/0192315, PCT International Application Publication Nos. WO 2005/074899, WO 2007/047863, and 2007/146248.

General techniques and compositions for making dosage forms useful in the present invention are described-in the following references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol 7. (David Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds.); Modern Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol. 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds.). These references in their entireties are hereby incorporated by reference into this application.

Tablets may contain suitable binders, lubricants, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. For instance, for oral administration in the dosage unit form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, microcrystalline cellulose and the like. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn starch, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, povidone, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, sodium benzoate, sodium acetate, sodium chloride, stearic acid, sodium stearyl fumarate, talc and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, croscarmellose sodium, sodium starch glycolate and the like.

TERMS

As used herein, and unless stated otherwise, each of the following terms shall have the definition set forth below.

As used herein, “laquinimod” means laquinimod acid or a pharmaceutically acceptable salt thereof.

As used herein, an “amount” or “dose” of an agent, e.g., laquinimod as measured in milligrams refers to the milligrams of the agent, e.g., laquinimod acid present in a preparation, regardless of the form of the preparation. A “dose of 0.6 mg laquinimod” means the amount of laquinimod acid in a preparation is 0.6 mg, regardless of the form of the preparation. Thus, when in the form of a salt, e.g. a laquinimod sodium salt, the weight of the salt form necessary to provide a dose of 0.6 mg laquinimod would be greater than 0.6 mg (e.g., 0.64 mg) due to the presence of the additional salt ion.

As used herein, a “unit dose”, “unit doses” and “unit dosage form(s)” mean a single drug administration entity/entities.

As used herein, “about” in the context of a numerical value or range means±10% of the numerical value or range recited or claimed.

As used herein, “effective” or “therapeutically effective” when referring to an amount of laquinimod or a therapy regimen using laquinimod refers to the quantity or regimen of laquinimod that is sufficient to yield a desired therapeutic response. Efficacy can be measured by an improvement of a symptom of multiple sclerosis. Such symptoms can include a MRI-monitored multiple sclerosis disease activity, relapse rate, accumulation of physical disability, frequency of relapses, time to confirmed disease progression, time to confirmed relapse, frequency of clinical exacerbation, brain atrophy, neuronal dysfunction, neuronal injury, neuronal degeneration, neuronal apoptosis, risk for confirmed progression, visual function, fatigue, impaired mobility, cognitive impairment, brain volume, abnormalities observed in whole Brain MTR histogram, general health status, functional status, quality of life, and/or symptom severity on work.

As used herein, “clinical responsiveness” is a measure of the degree of a patients' response to an agent, e.g., laquinimod. Positive clinical responsiveness corresponds to a patient who responds favorably to and/or benefits from receiving laquinimod (a laquinimod responder) while negative clinical responsiveness corresponds a patient who responds unfavorably to and/or does not benefit from receiving laquinimod (a laquinimod non-responder).

As used herein, “a gene associated with” a process or a system, e.g., a gene associated with inflammatory response or a gene associated with hematological system, is a gene which plays a role in that process or system. As an example, a gene associated with inflammatory response can be IL-1R, IL-8R, IL-22R, IL-9, TNFRSF4 or RORC.

Administering to the subject” or “administering to the (human) patient” means the giving of, dispensing of, or application of medicines, drugs, or remedies to a subject/patient to relieve, cure, or reduce the symptoms associated with a condition, e.g., a pathological condition. The administration can be periodic administration. As used herein, “periodic administration” means repeated/recurrent administration separated by a period of time. The period of time between administrations is preferably consistent from time to time. Periodic administration can include administration, e.g., once daily, twice daily, three times daily, four times daily, weekly, twice weekly, three times weekly, four times weekly and so on, etc.

“Treating” as used herein encompasses, e.g., inducing inhibition, regression, or stasis of a disease or disorder, e.g., Relapsing MS (RMS), or alleviating, lessening, suppressing, inhibiting, reducing the severity of, eliminating or substantially eliminating, or ameliorating a symptom of the disease or disorder. “Treating” as applied to patients presenting CIS can mean delaying the onset of clinically definite multiple sclerosis (CDMS), delaying the progression to CDMS, reducing the risk of conversion to CDMS, or reducing the frequency of relapse in a patient who experienced a first clinical episode consistent with multiple sclerosis and who has a high risk of developing CDMS.

“Inhibition” of disease progression or disease complication in a subject means preventing or reducing the disease progression and/or disease complication in the subject.

A “symptom” associated with MS or RMS includes any clinical or laboratory manifestation associated with MS or RMS and is not limited to what the subject can feel or observe.

As used herein, “a subject afflicted with multiple sclerosis” or “a subject afflicted with relapsing multiple sclerosis” means a subject who has been clinically diagnosed to have multiple sclerosis or relapsing multiple sclerosis (RMS), which includes relapsing-remitting multiple sclerosis (RRMS) and Secondary Progressive multiple sclerosis (SPMS).

As used herein, a subject at “baseline” is as subject prior to administration of laquinimod.

A “patient at risk of developing MS” (i.e. clinically definite MS) as used herein is a patient presenting any of the known risk factors for MS. The known risk factors for MS include any one of a clinically isolated syndrome (CIS), a single attack suggestive of MS without a lesion, the presence of a lesion (in any of the CNS, PNS, or myelin sheath) without a clinical attack, environmental factors (geographical location, climate, diet, toxins, sunlight), genetics (variation of genes encoding HLA-DRB1, IL7R-alpha and IL2R-alpha), and immunological components (viral infection such as by Epstein-Barr virus, high avidity CD4⁺ T cells, CD8⁺ T cells, anti-NF-L, anti-CSF 114(Glc)).

“Clinically isolated syndrome (CIS)” as used herein refers to 1) a single clinical attack (used interchangeably herein with “first clinical event” and “first demyelinating event”) suggestive of MS, which, for example, presents as an episode of optic neuritis, blurring of vision, diplopia, involuntary rapid eye movement, blindness, loss of balance, tremors, ataxia, vertigo, clumsiness of a limb, lack of co-ordination, weakness of one or more extremity, altered muscle tone, muscle stiffness, spasms, tingling, paraesthesia, burning sensations, muscle pains, facial pain, trigeminal neuralgia, stabbing sharp pains, burning tingling pain, slowing of speech, slurring of words, changes in rhythm of speech, dysphagia, fatigue, bladder problems (including urgency, frequency, incomplete emptying and incontinence), bowel problems (including constipation and loss of bowel control), impotence, diminished sexual arousal, loss of sensation, sensitivity to heat, loss of short term memory, loss of concentration, or loss of judgment or reasoning, and 2) at least one lesion suggestive of MS. In a specific example, CIS diagnosis would be based on a single clinical attack and at least 2 lesions suggestive of MS measuring 6 mm or more in diameter.

As used herein, a “multiple sclerosis drug” is a drug or an agent intended to treat clinically defined MS, CIS, any form of neurodegenerative or demyelinating diseases, or symptoms of any of the above mentioned diseases. “Multiple sclerosis drugs” may include but are not limited to antibodies, immunosuppressants, anti-inflammatory agents, immunomodulators, cytokines, cytotoxic agents and steroids and may include approved drugs, drugs in clinical trial, or alternative treatments, intended to treat clinically defined MS, CIS or any form of neurodegenerative or demyelinating diseases. “Multiple sclerosis drugs” include but are not limited to Interferon and its derivatives (including BETASERON®, AVONEX® and REBIF®), Mitoxantrone and Natalizumab. Agents approved or in-trial for the treatment of other autoimmune diseases, but used in a MS or CIS patient to treat MS or CIS are also included.

As used herein, a “naïve patient” is a subject that has not been treated with a multiple sclerosis drug as defined herein. Similarly, a patient or subject who is “naïve” to an agent, e.g., laquinimod, is a patient or subject that has not been treated with said agent.

As used herein, “in the blood of the subject” is represented by PBMCs, lymphocytes, monocytes, macrophages, basophils, dendritic cells or other cells derived from the subject's blood.

As used herein a “reference value” is a value or range of values that characterizes a specified population in a defined state of health.

A “pharmaceutically acceptable carrier” refers to a carrier or excipient that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio. It can be a pharmaceutically acceptable solvent, suspending agent or vehicle, for delivering the instant compounds to the subject.

It is understood that where a parameter range is provided, all integers within that range, and tenths thereof, are also provided by the invention. For example, “0.1-2.5 mg/day” includes 0.1 mg/day, 0.2 mg/day, 0.3 mg/day, 0.4 mg/day, 0.5 mg/day etc. up to 2.5 mg/day.

This invention will be better understood by reference to the Experimental Details which follow, but those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention as described more fully in the claims which follow thereafter.

Experimental Details Example 1 High-Through Output Gene Expression Ancillary Study for Phase III Clinical Trial (“ALLEGRO” or MS-LAQ-301) to Assess Effect of Laquinimod on Peripheral Blood Mononuclear Cells in Relapsing-Remitting Multiple Sclerosis

In a previous study by Gurevich et al. (Gurevich et al. 2010), in vitro molecular effects of laquinimod (LAQ) in peripheral blood mononuclear cells (PBMC) of healthy subjects and relapsing-remitting multiple sclerosis (RRMS) patients were characterized by gene expression microarrays. Gurevich et al. demonstrated that LAQ induced suppression of genes related to antigen presentation and corresponding inflammatory pathways. To further elucidate the molecular mechanism/s underlying the therapeutic effect of LAQ following treatment of patients displaying RRMS, the inventors performed gene expression microarray analysis of PBMCs from RRMS patients treated with LAQ as ancillary study to ALLEGRO clinical trial.

ALLEGRO Clinical Trial

ALLEGRO was a multinational (24 countries), multicenter (approximately 139 sites), randomized, double-blinded, parallel-group, placebo-controlled clinical trial conducted to evaluate the efficacy, safety and tolerability of daily oral administration of laquinimod 0.6 mg in subjects with relapsing remitting multiple sclerosis (RRMS) for a 24 months duration.

One thousand one hundred and six (1106) patients were equally randomized to either laquinimod 0.6 mg or placebo and treated in a double-blind manner and baseline characteristics were balanced between groups. The primary endpoint of the study was the number of confirmed relapses during the double-blind treatment period, which corresponds to the annualized relapse rate (ARR—number of relapses divided by total exposure of all patients). Secondary endpoints included disability as measured by Expanded Disability Status Scale (EDSS) changes confirmed at 3 months, and cumulative number of gadolinium enhancing (GdE) and new/enlarging T2 MRI lesions.

Study Duration

Screening phase: 1 month.

Double blind treatment phase: 24 months of once-daily oral administration of daily dose of 0.6 mg laquinimod or matching placebo.

Upon blinded variance and power reassessment of the population progression (planned prior to first subject completes the 20 months of treatment), the double blind study duration may be extended to 30 months. This is planned in order to enhance the statistical power to detect the effect of laquinimod on disability accumulation. The recommendation to extend the study duration is based on a pre-defined rule.

Study Design

Eligible subjects were equally randomized 1:1 into one of the following treatment arms:

-   1. Laquinimod capsules 0.6 mg: One 0.6 mg laquinimod capsule was     administered orally once daily. The 0.6 mg laquinimod capsules     contain 0.6 mg of Laquinimod Acid per capsule with meglumine, and     were manufactured according to the method disclosed in PCT     International Application Publication No. WO/2007/146248, published     Dec. 21, 2007 (see, page 10, line 5 to page 11, line 3). -   2. Matching placebo for laquinimod arm: one capsule is administered     once daily.

Subjects were evaluated at study sites for 12 scheduled visits of the double blind phase at months: −1 (screening), 0 (baseline), 1, 2, 3, 6, 9, 12, 15, 18, 21 and 24 (termination/early discontinuation). In case of the 6 months extended study, subjects were evaluated at study sites at months 27 and 30 (termination/early discontinuation of extended study), in this case month 24 was a regular scheduled visit.

EDSS was assessed every 3 months, MSFC every 6 months, and MRI was performed annually in all patients. A subgroup of patients (n=189) underwent additional MRI scans at months 3 and 6. Subjects successfully completing the study were offered the opportunity to enter into a 1-year open label extension. Patients who discontinued the study underwent a final termination visit and were not further evaluated, except for those who discontinued due to adverse events.

The following assessments were performed at specified time points:

-   1. Vital signs were measured at each study visit. -   2. A physical examination is performed at months −1 (screening), 0     (baseline) 1, 3, 6, 12, 18 and 24 (termination/early discontinuation     core study). In case of the 6 months extended study, additional     examination was performed at month 30 (termination/early     discontinuation of extended study). -   3. The following safety clinical laboratory tests were performed:     -   a. Complete blood count (CBC) with differential—at all scheduled         visits. A reticulocyte count was added to the CBC at months 0         (baseline) and 24/30 (termination/early discontinuation).     -   b. Serum chemistry (including electrolytes, liver enzymes,         direct and total bilirubin and pancreatic amylase and CPK), and         urinalysis—at all scheduled visits.     -   c. A rapid urine β-hCG test was performed in women of         child-bearing potential at baseline (month 0) and at each         scheduled study visit thereafter (at site).     -   d. β-hCG in women of child-bearing potential was performed at         all scheduled visits.     -   e. Starting after visit Month 3 a rapid urine β-hCG test was         performed in women of child-bearing potential every 28 (±2)         days. The subject was contacted by telephone within 72 hours         after the test was scheduled to be performed and asked specific         questions regarding the test. In case of suspected pregnancy         (positive urine fi-hCG test result), the caller made sure that         the study drug has been discontinued and the subject was         instructed to arrive at the site as soon as possible with all         study drugs. -   4. Markers of inflammation (serum conventional C-reactive protein     and fibrinogen)—at screening, baseline and all scheduled visits     thereafter. -   5. During the first 3 months periodical phone calls were placed by     the site personnel every two weeks. A list of predefined questions     relating to signs/symptoms suggestive of vascular thrombosis was     presented to the subjects. -   6. ECG was performed at months −1 (screening; additional recording,     up to 30 minutes apart is performed if QT_(c) is less than 450     msec), (baseline; three recordings, 15 minutes apart), 1, 2, 3, 6,     12, 18 and 24 (termination/early discontinuation). In case of the 6     months extended study, ECG is performed at month 30     (termination/early discontinuation of the extended study). -   7. Chest X-ray is performed at months −1 (screening), (if not     performed within 7 months prior to the screening visit). -   8. Adverse Events (AEs) are monitored throughout the study. -   9. Concomitant medications are monitored throughout the study. -   10. Neurological evaluations, including Expanded Disability Status     Scale (EDSS), 25 foot walk test/Ambulation Index (AI), Functional     systems (FS) are performed at months −1 (screening), 0 (baseline)     and every 3 months during the study and the extended study period. -   11. MS functional Composite (MSFC) was assessed at months −1     (screening) (three practices for training purposes only), at month 0     (baseline), 6, 12, 18 and 24 (termination/early discontinuation). In     case of the 6 months extended study, the last MSFC was performed at     months 30 (termination/early discontinuation of the extended study). -   12. Subject-reported fatigue was assessed by the Modified Fatigue     Impact Scale (MFIS) at months 0, 6, 12, 18, and 24     (termination/early discontinuation). In case of the 6 months     extended study, additional MFIS was performed at month 30     (termination/early discontinuation of the extended study). -   13. The general health status was assessed by the EuroQoL (EQ5D)     questionnaire at month 0 (baseline) and month 24 (termination/early     discontinuation of the study). In case of the 6 months extended     study, the last EuroQoL (EQ5D) was performed at month 30     (termination/early discontinuation of the extended study) instead of     month 24. -   14. The general health status was assessed by the Short-Form general     health survey (SF-36) subject-reported questionnaire at month 0     (baseline) and every 6 months thereafter, until termination/early     discontinuation. -   15. The subject underwent 5 assessments of binocular low-contrast     visual acuity using the 100%, 2.5% and 1.25% contrast level charts     [Sloan letter or Tumbling-E] in each assessment, at months 0     (baseline), 6, 12, 18 and 24 (termination/early discontinuation). In     case of extending the study for 6 months, additional binocular     low-contrast visual acuity assessment is performed at month 30     (termination/early discontinuation of the extended study). -   16. Serum samples were collected from all subjects in order to     investigate the potential mechanism of action of laquinimod and     additional biomarkers of inflammation and potential biomarkers of MS     disease at months: 0, 1, 12 and 24. In case of extending the study     for 6 months the last serum sample is performed at month 30     (termination/early discontinuation of the extended study) instead of     month 24. -   17. The subjects underwent 3 MRI scans at months 0 (baseline), 12     and 24 (termination/early discontinuation). In case of the 6 months     extended study, an additional MRI was performed at month 30     (termination/early discontinuation of the extended study). -   18. Population PK study (PPK): Blood samples for PPK evaluation were     collected from all subjects at months 1, 12 and 24. In case of     extending the study for 6 months the last PPK evaluation was     performed at month 30 (termination/early discontinuation of the     extended study) instead of month 24. -   19. Relapses were confirmed/monitored through the study. Since the     “in study” relapse definition must be supported by an objective     neurological evaluation, a neurological deficit must sustain long     enough to eliminate pseudo-relapses. Therefore, in this clinical     trial, a relapse was the appearance of one or more new neurological     abnormalities or the reappearance of one or more previously observed     neurological abnormalities wherein the change in clinical state     lasts at least 48 hours and is immediately preceded by an improving     neurological state of at least thirty (30) days from onset of     previous relapse. -   20. The allowed treatment for a relapse was intravenous     Methylprednisolone 1 gr/day for up to 5 consecutive days.

Inclusion/Exclusion Criteria Inclusion Criteria

-   1. Subjects must have a confirmed and documented diagnosis as     defined by the Revised McDonald Criteria (Polman, 2005), with     relapsing-remitting disease course. -   2. Subjects must be ambulatory with converted Kurtzke EDSS score of     0-5.5. -   3. Subjects must be in a stable neurological condition and free of     corticosteroid treatment [intravenous (iv), intramuscular (im)     and/or per os (po)]30 days prior to screening (month −1). -   4. Subjects must have experienced one of the following:     -   a. At least one documented relapse in the 12 months prior to         screening.     -   b. At least two documented relapses in the 24 months prior to         screening.     -   c. One documented relapse between 12 and 24 months prior to         screening with at least one documented T1-Gd enhancing lesion in         an MRI performed within 12 months prior to screening. -   5. Subjects must be between 18 and 55 years of age, inclusive. -   6. Subjects must have disease duration of at least 6 months (from     the first symptom) prior to screening. -   7. Women of child-bearing potential must practice an acceptable     method of birth control. Acceptable method of birth control in this     study include: surgical sterilization, intrauterine devices, oral     contraceptive, contraceptive patch, long-acting injectable     contraceptive, partner's vasectomy or double barrier method (condom     or diaphragm with spermicide). -   8. Subjects must be able to sign and date a written informed consent     prior to entering the study. -   9. Subjects must be willing and able to comply with the protocol     requirements for the duration of the study.

Exclusion Criteria

-   1. Subjects with progressive forms of MS. -   2. An onset of relapse, unstable neurological condition or any     treatment with corticosteroids [(iv), intramuscular (im) and/or per     os (po)] or ACTH between months −1 (screening) and 0 (baseline). -   3. Use of experimental or investigational drugs, and/or     participation in drug clinical studies within the 6 months prior to     screening. -   4. Use of immunosuppressive including mitoxantrone (Novantrone®) or     cytotoxic agents within 6 months prior to screening visit. -   5. Previous use of any one of the following: natalizumab (Tysabri®),     caldribine, laquinimod. -   6. Previous treatment with glatiramer acetate (Copaxone®)     Interferon-β (either 1a or 1b) or intravenous immunoglobulin (IVIG)     within 2 months prior to screening visit. -   7. Systemic corticosteroid treatment of ≧30 consecutive days     duration within 2 months prior to screening visit. -   8. Previous total body irradiation or total lymphoid irradiation. -   9. Previous stem cell treatment, autologous bone marrow     transplantation or allogenic bone marrow transplantation. -   10. A known history of tuberculosis. -   11. Acute infection two weeks prior to baseline visit. -   12. Major trauma or surgery two weeks prior to baseline. -   13. Use of inhibitors of CYP3A4 within 2 weeks prior to baseline     visit (1 month for fluoxetine). -   14. Use of amiodarone within 2 years prior to screening visit. -   15. Pregnancy or breastfeeding. -   16. A ≧3xULN serum elevation of either ALT or AST at screening. -   17. Serum direct bilirubin which is ≧2xULN at screening. -   18. A QTc interval which is 450 msec (according to machine output)     obtained from:     -   a. Two ECG recordings at screening visit, or     -   b. The mean value calculated from 3 baseline ECO recordings. -   19. Subjects with clinically significant or unstable medical or     surgical condition that would preclude safe and complete study     participation, as determined by medical history, physical     examination, ECG, laboratory tests or chest X-ray. Such conditions     may include:     -   a. A cardiovascular or pulmonary disorder that cannot be         well-controlled by standard treatment permitted by the study         protocol.     -   b. A gastrointestinal disorder that may affect the absorption of         study medication.     -   c. Renal or metabolic diseases.     -   d. Any form of chronic liver disease.     -   e. Known human immunodeficiency virus (HIV positive status.     -   f. A family history of Long-QT syndrome.     -   g. A history of drug and/or alcohol abuse.     -   h. Major psychiatric disorder. -   20. A known history of sensitivity to Gd. -   21. Inability to successfully undergo MRI scanning. -   22. Known drug hypersensitivity that would preclude administration     of laquinimod, such as hypersensitivity to: mannitol, meglumine or     sodium stearyl fumarate.

Ancillary High-Through Output Gene Expression Study

The goal of this ancillary study was to characterize gene expression changes and corresponding biological mechanisms induced in PBMC of RRMS patients by LAQ treatment. According to ALLEGRO clinical trial inclusion criteria, 25 patients were randomly assigned to receive LAQ (n=13, age 38.8±2.3 years, female/male ratio: 8/5) or placebo (n=12, age 37.2±3.4 years, female/male ratio: 8/4).

Peripheral blood samples were obtained from RRMS patients at baseline before start of LAQ treatment or placebo, after 0, 1, 6 and 24 month of treatment (visit 0, 1, 6 and 7 according to ALLEGRO clinical trial protocol correspondently) for gene microarray analysis.

Briefly, 1) Peripheral blood mononuclear cells (PBMC) were obtained from RRMS patients that participated in ALLEGRO and were treated daily with 0.6 mg LAQ or placebo. PBMC were subjected for gene expression analysis (HU-133A-2-Affymatrix arrays) at baseline and at 1 and 6 months of LAQ treatment; 2) Data was analyzed by Partek Genomics Solution software. Most informative genes (MIGs) were defined as those that differentiated between groups with p<0.01. Gene functional annotation, enrichment and pathway analysis were performed by Ingenuity software. For each time point, genes that changed in placebo group were excluded from further analysis; and 3) Verification of LAQ related mechanism was performed by Western blot.

LAQ was found to induce a differential gene expression of 354 MIGs at 1 month and 1562 MIGs at 6 months of treatment.

This study shows that LAQ down-regulates genes associated with adhesion, migration and chemotaxis of PBMC either directly or via TGFb suppression. These effects were observed after 1 and strengthened after 6 month of LAQ treatment. LAQ also down-regulates PAI-1 suggesting activation of fibrinolysis and possibly subsequent neuroprotection. Both effects can contribute to amelioration of MS clinical symptoms.

RNA Isolation and Hybridization

PBMC were extracted from 15 ml peripheral blood, separated by Ficoll-Hypaque gradient. Total RNA was extracted using both Trizol (Invitrogen, USA) and Phase-Lock-Gel columns (Eppendorf, Germany) including a DNase digestion step. RNA integrity was assessed by RNA Experion automated electrophoresis system (Bio-Rad Laboratories, Hercules, Calif.).

Probe synthesis using 3 μg total RNA, hybridization, detection, and scanning was performed according to the standard Affymetrix, Inc. USA protocols; cDNA was synthesized using the Two-Cycle cDNA Synthesis Kit (Affymetrix, Inc., USA), and in-vitro transcription performed with the GeneChip IVT Labeling Kit (Affymetrix, Inc., USA). The biotin-labeled IVT-RNA was hybridized to HG-U133A-2 arrays containing 18,400 gene transcripts, each corresponding to 14,500 well-annotated human genes, washed in a GeneChip Fluidics Station 450 (Hewlett Packard, USA, GeneArray-™ scanner G2500A) and scanned according to the manufacturer's protocol (Affymetrix, Inc., USA).

Data Analysis

Data analysis was performed on Partek Genomics Solution software (www.partek.com; Partek Incorporated, St. Louis, Mo.). Expression values were computed from raw CEL files by applying the Robust Multi-Chip Average (RMA) background correction algorithm. RMA correction included: 1) values background correction; 2) quintile normalization; 3) log 2 transformation; and 4) median polish summarization. The ANOVA, Repeated Measures and correlation analysis implicated in Partek software ware applied to evaluate LAQ effects. Most informative genes MIGs were defined as those that differentiated between experimental groups with p<0.01. All p-values were calculated for False Discovery Rate (FDR) multiple test correction at p=0.05.

Additionally, significance of individual genes was tested by parametric T-test and non parametric Mann-Whitney test using Bootstrapping approach based on repeated permutations of the data with 5% FDR for multiple testing.

Gene functional annotation, enrichment, and pathway analyses to identify the leading biological pathways that operated under LAQ treatment were performed by Ingenuity Pathways Analysis software (www.ingenuity.com). Enrichment was defined as significantly (p<0.05) higher proportion of genes than expected by chance in a given gene set.

Western Blot Analysis

For verification of key genes on protein level Western blot analysis was performed. Supernatant was collected and protein concentration was determined using a Bradford assay (Pierce, Rockford, Ill., USA) according the manufacturer's guidelines. Equal amounts of protein were suspended in sample buffer and boiled for 5 min. Cell lysates were resolved on 10% SDS-polyacrylamide gel electrophoresis (PAGE). Gels were transferred to a Nitrocellulose membrane (Amersham, Buckinghamshire, UK), blocked with 1% BSA in Tris-buffered saline Tween (TBST) buffer (20 mM Tris, 137 mM NaCl and 0.1% Tween 20) and incubated with primary antibody overnight at 4° C. After washing three times with TBST buffer, blots were incubated with alkaline peroxidase-conjugated secondary antibody. Antibodies were diluted in the blocking solution. The blots were then washed three times with TBST buffer and analyzed by standard chemiluminescence (Supersignal Kit, Pierce, Rockford, Ill., USA) according to the company's protocol.

Results

According to ancillary study aims, 72 blood samples were collected. The number of samples and corresponding demographical data is presented in Table 1.

TABLE 1 Clinical and demographical data of subjects Visit(Month) 0(0) 1(1) 4(6) 7(24) N of patients 21 23 17 11  LAQ(N) 12 13 12 8 Placebo(N) 9 10  5 3 age 38.07 ± 2.20 36.66 ± 1.93 38.17 ± 2.39 40.25 ± 2.84 N(%) male  7/21(33.33%) 8/23(34.78%) 7/17(41.18%) 5/11(45.45%) N(%) female 14/21(66.67%) 15/23(65.22%)  10/17(58.82%)  6/11(54.55%) LAQ N(%) male 5/12(41.67%) 5/13(38.46%) 5/12(41.67%) N(%) Female 7/12(58.33%) 8/13(61.54%) 7/12(58.33%) Placebo N(%) male  2/9(22.22%) 3/10(30.00%)  2/5(40.00%) N(%) Female  7/9(77.78%) 7/10(70.00%)  3/5(60.00%)

ANOVA Analysis

ANOVA analysis was used to compare PBMC gene expression after 1, 6 or 24 month of LAQ treatment with baseline gene expression.

For each time point inventors performed analysis source of variation in dataset. (FIG. 1). Age, gender and batch effects were considered as confounders regarding LAQ or Placebo related changes. For each time point genes associated with Placebo effect were evaluated and excluded from further analysis.

Table 2 below shows number of genes significantly changed by ANOVA test in each time point as compared with baseline.

TABLE 2 Number of LAQ related MIGs according to ANOVA p values. Visits according to # of genes Down Up- Time Point protocol p < 0.01 regulated regulated FDR 1 month 1 354 348 6 No 6 month 4 1562 1552 10 43 6 and 24 4 and 7 2922 2911 11 1564 month

Table 3 and Table 4 below shows the main biological pathways and functions affected by LAQ.

TABLE 3 Main biological pathways and functions affected by LAQ After one month of treatment After six months of treatment genes p- genes p- function pathway (#) value function pathway (#) value Inflammatory Adhesion of 9 1.2*10⁻³ Development G protein 73 3.1*10⁻⁵ response phagocytes Coupled Receptor Signaling Chemotaxis 4 6.0*10⁻³ Arachidonic 18 2.2*10⁻³ of Neutrophils Acid metabolism Transmigration 8 1.9*10⁻³ TGFB 14 4.3*10⁻² of signaling leukocytes Caveolar 8 1.8*10⁻⁴ Inflammatory Leukocyte 29 9.4*10⁻³ mediated response Extravasation endocytosis Signaling Clathrin 12 2.1*10⁻⁴ Caveolar 13 2.1*10⁻² mediated mediated endocytosis endocytosis Hematological Aggregation 18  3.5*10⁻¹⁰ Cell Adhesion of 119 2.4*10⁻⁵ system of blood signaling cells platelets Activation of 13 1.4*10⁻⁸ Neuro- 56 2.1*10⁻⁵ blood transmission platelets Aggregation 19 2.6*10⁻⁸ Hematological Intrinsic 6 6.2*10⁻² of blood cells system prothrombin activation pathway Coagulation 14 7.4*10⁻⁷ Coagulation 7 7.4*10⁻² of blood system

TABLE 4 Main biological pathways and functions affected by LAQ After one month of treatment After six months of treatment genes p- genes p- function pathway (#) value function pathway (#) value Inflammatory TGFb 10 3.2*10⁻³ Inflammatory TGFb 14 3.7*10⁻² response signaling response signaling IL-12 11 3.2*10⁻³ signaling Cellular Adhesion & 9 1.2*10⁻³ Cellular Invasion of 120 5.6*10⁻⁵ Movement migration of movement cells phagocytes Chemotaxis of 4 6.0*10⁻³ Adhesion 119 2.4*10⁻⁵ neutrophils of cell Transmigration 8 1.9*10⁻³ Leukocyte 31  4*10⁻³ of leukocytes extravasation signaling

The majority of genes that showed significant changes at each time points were down regulated. The functional enrichment analysis of 354 genes affected after 1 month of treatment showed suppression of 50 molecules associated with different mechanisms of inflammatory response (p value from 3.4*10⁻¹⁰ to 1.1*10⁻²). This included for example suppression of adhesion of phagocytes (p=1.2*10⁻³) and chemotaxis of neutrophils (p=6.0*10⁻³) based on suppression of TGFB1, ITGB1, ITGB3, ITGB5 and CXCL5, ITGB1, MMP1, TGFB1 correspondently. The most significant canonical pathways are suppression of Caveolar and Clatrin mediated Endocytosis Signaling (p=1.8*10⁻⁴ and 2.1*10⁻⁴). The interesting findings are suppression of PTCR and CD84 that function in adhesion interaction between T lymphocytes and accessory cells.

As shown in Table 2 the number of genes significantly affected by LAQ (p<0.01) changed from 354 to 1562 between 1 and 6 months of treatment, and 43 genes passed stringent FDR criteria for 6 months of treatment (FIG. 2A). Total 260 genes out of 1562 were related to suppression of Cellular movement functions (p value of enrichment from 4.6*10⁻⁷ to 5.4*10⁻³). G protein Coupled Receptor Signaling (p=3.1*10⁻⁵), Arachidonic Acid metabolism (p=2.2*10⁻³), Leukocyte Extravasation Signaling (p=9.4*10⁻³), Caveolar mediated endocytosis Signaling (p=2.1*10⁻²), TGF beta Signaling (p=4.3*10⁻²), Adhesion of cells (p=2.4*10⁻⁵), Neurotransmission (p=2.1*10⁻⁵), Intrinsic prothrombin activation pathway (p=6.2*10⁻²) and Coagulation system (p=7.4*10⁻²) were the most significantly down-regulated canonical pathways after 6 months of treatment.

The number of patients involved in analysis at 24 months of treatment was relatively low, thus in order to improve statistical power, the inventors combined data from 6 and 24 months which resulted in evaluation of 2922 genes with p<0.01 and 1564 genes that passed FDR criteria (FIG. 2B). Due to high statistical significance of combined 6 and 24 months LAQ signature the most detailed functional analysis was applied.

LAQ Down-Regulates Expression of Migration/Adhesion Molecules

Functional analysis of 1564 genes that passed FDR criteria after more than 6 months of treatment showed significant enrichment of down-regulated genes (n=305) related to different kind of cellular movement mechanisms with p values from 1.5*10⁻³ to 4.5*10⁻¹⁴. This included for example suppression of cell migration function (n=233, p=4.5*10⁻¹⁴) and chemotaxis (n=78, p=4.3*10⁻⁵).

LAQ significantly down-regulated a range of Metalloproteinase family members such as MMP1, MMP14, MMP16, MMP24, MMP25, MMP26, MMP28, ADAM12 and ADAM22. Several Integrin and chemokine related genes were down-regulated upon treatment of LAQ: ITGB1, ITGB5, ITGB6, ITGA8, ITGB8, and GPIIB-III3 (fibrinogen receptor), CXCL4, CCL14, CCL18, CCXCR1 (XCR1), CXCL7 (PPBP).

These results are in line with previous studies reporting that LAQ interferes with the migratory capacity of T cells in mice with EAE (Wegner et al., 2010, Jadidi-Niaragh et al., 2011).

LAQ Down-Regulates Pro-Inflammatory Constituents

In addition to suppression of cell migration ability, treatment of LAQ demonstrated significant down-regulation of IL-1R, IL-8R and IL-22R, IL-9, TNFRSF4, and RORC (RORgamma), all of which are inflammation-related genes that are known to play a role in EAE (Jadidi-Niaragh et al., 2011). Recently, it has been shown that IL-9 is important for T-cell activation and differentiation in autoimmune inflammation of the CNS, and that IL-9−/− mice developed significantly less severe EAE than their WT counterparts (Li et al., 2011). The results show reduced expression of SOCS (suppressor of cytokine signaling), a negative regulator of immune response, which is indirectly regulated by TGFb1 and ICOSLG (inducible T-cell co-stimulator ligand). In correlation with down-regulation of the pro-inflammatory constituents, LAQ treatment significantly reduced the expression of CSF1, CSF2 and CSF3 and indirectly affected FoxP3 expression. ROR (RORgamma) can directly interact with FoxP3. However, the functional consequence of this interaction is not clear because none of the previous studies on LAQ effect described an effect on Treg. Clatrin and Caveolar-mediated Endocytosis pathways are significantly suppressed (p=5.0*10⁻⁴ and p=5.8*10⁻⁴) after 1 month of treatment.

TGFB1 Related Mechanism

6 months or longer treatment of LAQ induced significant suppression of genes related to the TGFB pathway (p=1.9*10⁻²) (FIG. 3)

TGFB is a potent regulatory cytokine with diverse effects on hematopoietic cells. The pivotal function of TGFB in the immune system is to maintain tolerance via the regulation of lymphocyte proliferation, differentiation, and survival. Among T cells, CD4+CD25+FOXP3+ T regs contain the main source of TGFB that suppresses immune responses in inflammatory sites. Defects in TGFB1 expression or its signaling in T cells correlate with the onset of several autoimmune diseases. It has been shown previously that besides its anti-inflammatory role, TGFB paradoxically acts as a pro-inflammatory cytokine and induces IL-17-producing pathogenic T helper cells (Th IL-17 cells) during an inflammatory response in which IL-6 is produced (Mirshafiey and Mohsenzadegan, 2009) (FIG. 4). Consistent with the proposed pro-inflammatory role of TGFB our analysis showed down-regulation of several TGFB-related genes and its downstream signaling components including: LTBP1 (latent transforming growth factor beta binding protein 1), Type I receptor, Smad2/3, Smad4, TCF [hepatocyte nuclear factor 4 alpha (HNF4A)] and PAI-1 (FIG. 3).

Western blot analyses in four out of five patients who received 6 months of LAQ treatment verified down-regulation of TGFB1 protein level by 20-50%, as shown by quantification of band intensities normalized against Tubulin (FIGS. 5A and 5B).

LAQ Induced Down-Regulation of Serpine 1 [(Plasminogen Activator Inhibitor 1(PAI-1)] and Other Members of the Coagulation System

While anti-inflammatory properties of LAQ were previously reported (Gurevich et al., 2010, Brück and Wegner, 2011), the current study demonstrated down-regulation of several members of the coagulation pathway including F2 (thrombin), F7 (factor VII), F10 (factor X), FGB (fibrinogen beta-chain), TFPI [(tissue factor pathway inhibitor (lipoprotein-associated coagulation inhibitor)], Serpine 1 [plasminogen activator inhibitor (PAI-1)] and also two other members of the Serpine 1 family (SerpinA3 and SerpinB3). PAI-1 inhibits the serine proteases tissue plasminogen activator (tPA) and uPA/urokinase, thus it is an inhibitor of fibrinolysis, the physiological process that degrades blood clots. Although the tPA-plasmin cascade promotes neurodegeneration in excitotoxin-induced neuronal death, it has been demonstrated to have a protective role in inflammatory conditions with BBB disruption by removing fibrin, which exacerbates axonal injury (Gveric et al., 2003). Moreover, in the mouse model of MS, EAE incidence and clinical severity were reduced in PAI-1−/− mice, where clinical relapses were absent in PAI-1−/− mice and the subsequent reduction in neuroinflammation was coupled with a higher capacity for fibrinolysis in spinal cord samples from PAI-1−/− mice, in association with increased tPA activity (East et al., 2008).

Importantly, consistent with our gene expression results, which shows significant down-regulation of PAI-1, the Western blot analysis shown in FIG. 6 demonstrates reduced expression of PAI-1 protein by 30-50% in four out of five patients after 6 months of LAQ treatment. The quantification of band intensities were normalized against tubulin. Previous gene expression analysis of PBMCs treated in vitro with LAQ, also showed significant down-regulation of PAI-1 (Gurevich et al., 2010). These results suggest positive correlation between LAQ-induced down-regulation of TGFB1 and PAI-1 expression and implicate LAQ in suppression of the neurodegenerative role of PAI-1, as demonstrated by East et al., 2008 and Overic et al., 2003. The proposed mechanism of LAQ effects on PBMS is shown in FIG. 8A and FIG. 8B.

Correlation and Repeated Measures Analysis.

In ANOVA model each patients has to be independent under each condition. However in repeated measures algorithm the independence requirement is removed and each patients can repeatedly tested in different condition and responses from the same patients are correlated. Repeated measures increase statistical power and thus fewer subjects are needed to have adequate power. The inventors applied repeated measures analysis to evaluated effect of LAQ in same patients across all visits (28 microarrays related to 7 patients). First, using this approach the inventors evaluated Placebo effects and excluded placebo related genes from further analysis. The effect of LAQ realized in significant changing of 174 genes that pass FDR criteria with p<0.0004. Functional analysis of this gene list confirmed ANOVA results and among other included PTCRA, ITGB3, ITGA2B, ITGB5, PF4 and TGFB1 genes. The same of those gene profiles demonstrated in FIG. 7

Summary

In vivo effects of LAQ on PBMC showed down-regulation of genes as shown in Tables 3 and 4, including genes involving cell motility, adhesion, chemotaxis, IL1 and IL8 mediated inflammation, and Clatrin and Caveolar-mediated Endocytosis pathways, etc.

Functional enrichment analysis of most informative genes at 1 month of LAQ treatment demonstrated down-regulation of genes associated with inflammatory response, genes associated with TGFb signaling including TGFb1, TGFb1I1 and LTBP1 (p value range=3.8*10⁻⁴ to 6.7*10⁻³), (see Table 4) and other genes associated with cellular movement and migration (TNFSF4, SELP, ITGA8, ITGB1/3/5, CXCL5/7 and BMP6 genes).

Suppression of inflammation was further strengthened after 6 months of LAQ treatment, where there was suppression of large number of genes associated with adhesion, migration and leukocyte extravasation signaling (ITGA2/8, ITGb1/3/4/5/6, ITGBL1, MMP16/24/26/28 and ADAM12/18/22) accompanied by suppression of IL-1/5/8/13/20/22R, IL-9/11/12/36, TNFRSF11A/B, and IFNA4/8/10/17. Notably, LAQ treatment also down-regulated TGFB expression including its downstream signaling constituents (LTBP4, MEK1/2, TGFB type I receptor and smad2/3/4). Laquinimod treatment down-regulated TGFb expression including its associated signaling constituents (LTBP4, type II BMPR and smad1/4/5/6/8) and the NFkB signaling constituents (IL-1, IL-1R and IKKg) (see, FIG. 9A). Interestingly, the final downstream affected molecule in the TGFb pathway is the ITGB1 constituent of several Integrins that participates in rolling, adhesion, activation and locomotion and thereby regulates cellular movement in concert with CCL19, MMPs and ADAMs. The suppression of TGFB and ITGB1 was confirmed by Western blot (see FIG. 5). The proposed mechanism of Laquinimod effects on PBMC is depicted in FIG. 8A and FIG. 8B. The underlying mechanism of LAQ treatment is characterized by down-regulation of Serpine 1 (Plasminogen activator inhibitor 1, PAI-1), a potent inhibitor of fibrinolysis and the final downstream molecule affected in the TGFB pathway, and other members of the coagulation system. These results suggest that in addition to its ability to modulate cytokines expression and adhesion/migration, LAQ also modulates the coagulation pathway, contributes to fibrinolysis (by effective fibrin removal) and thereby reduces neuronal damage. The majority of changes described in this report could be explained by considerable suppression TGFB1 mechanism.

Conclusion

-   -   Laquinimod suppresses inflammation as shown by down-regulation         of genes of pro-inflammatory cytokines, TGFb and NFkB pathways.     -   Laquinimod suppresses the entire set of genes associated in the         multistep paradigm of leukocyte extravasation suggesting its         capability to inhibit infiltration of inflammatory cells to the         CNS.     -   These effects on inflammation and cell movement occurred either         directly or via TGFb suppression were observed after one month         and strengthened after six months of Laquinimod treatment.     -   The down-regulation of TGFb, NFkB and cellular movement         components by Laquinimod strongly suggests diminished CNS         infiltration and subsequent reduction in axonal damage which may         contribute to the therapeutic benefits of laquinimod in         amelioration of MS clinical symptoms.

Example 2 The Role of Laquinimod in Modulation of the Immune Response in Relapsing-Remitting Multiple Sclerosis: Lessons from Gene Expression Signature Abstract

The inventors analyzed the molecular pathways induced by LAQ treatment in patients that participated in the ALLEGRO trial using gene expression microarray analysis. Blood transcriptional changes after one and six months of treatment were compared to baseline to identify LAQ induced MIGs (p<0.01) and operating pathways.

The inventors identified 354 MIGs at one month and 1562 MIGs at six months of treatment. LAQ treatment effects were enhanced by duration of treatment and characterized by down-regulation of inflammatory responses via TGFb and NFkB signaling in combination with suppression of genes associated with cellular movement including adhesion, migration and leukocyte extravasation signaling like integrins, chemokines and metalloproteinases with further down-regulation of genes encoding pro-inflammatory cytokines.

These results demonstrate that LAQ acts via suppression of inflammation mainly through arrest of leukocytes extravasation and thereby could contribute to amelioration of disease activity in RRMS patients.

1. Introduction

LAQ was demonstrated to inhibit the development of acute experimental autoimmune encephalomyelitis (EAE) and to reduce EAE clinical score in mice treated after disease onset (Brück and Wegner, 2011; Brunmark et al., 2002; Jolivel et al., 2013; Ruffini et al, 2013; Schulze-Topphoff et al., 2012; Wegner et al., 2010). Clinically, LAQ demonstrated about 40% reduction in the cumulative number of gadolinium enhanced lesions in brain MRI in 106 RRMS patients as compared to 102 placebo treated RRMS patients (Comi et al., 2008). Recently, the Assessment of Oral Laquinimod in Preventing Progression in Multiple Sclerosis (Filippi et al., 2014) study demonstrated that LAQ treatment modestly decreased annualized relapse rate, slowed progression of disability and prevented white and gray matter atrophy in RRMS patients treated for 24 months (Comi et al., 2008; Filippi et al., 2014).

The mechanisms by which LAQ suppresses the development of EAE involve modulation of Th1/Th2 response, interference with the migration capacity of T cells (Bruck and Vollmer, 2013; Brück and Wegner, 2011; Wegner et al., 2010; Yang et al., 2004; Zou et al., 2002), and prevention of inflammation-induced synaptic alterations occurring in EAE (Ruffini et al., 2013). In addition, in MS patients, it has been reported that LAQ modulates B cells and their regulatory effects on T cells (Toubi et al., 2012), and down-regulates immunogenicity of dendritic cell (Jolivel et al., 2013).

In a previous study (Gurevich et at, 2010), the inventors characterized the molecular effects of LAQ in-vitro in separated immune cells subtypes obtained from RRMS patients using gene expression microarrays. The inventors demonstrated that LAQ induced suppression of genes related to antigen presentation and corresponding inflammatory pathways involving NFkB signaling, pleiotrophin-induced inflammatory cytokines, chemokine and toll like receptor signaling, down-regulation of Th2 response in CD14+ macrophages and CD4+ T cells, suppression of proliferation in CD8+ T cells, and suppression of antigen presentation and adhesion in CD19+ B cells via suppression of NFkB pathway.

To further elucidate the molecular mechanisms underlying the therapeutic effects of LAQ in RRMS, the inventors performed high throughput gene expression microarray analysis of PBMCs from RRMS patients that participated in the ALLEGRO trial.

2. Methods

Peripheral blood samples were obtained from RRMS patients treated with LAQ 0.6 mg/day or placebo as an ancillary study to the Assessment of Oral Laquinimod in Preventing Progression in Multiple Sclerosis trial (Filippi et al., 2014). Blood samples were obtained at baseline and after one and six months of treatment.

2.1. RNA Isolation and Hybridization

PBMC were extracted from 15 ml peripheral blood, separated by Ficoll-Hypaque gradient. Total RNA was extracted using both Trizol including a DNase digestion step. RNA integrity was assessed by RNA Experion automated electrophoresis system. Probe synthesis using 3 μg total RNA, hybridization, detection, and scanning was performed according to the standard Affymetrix, Inc. USA protocols; cDNA was synthesized using the Two-Cycle cDNA Synthesis Kit (Affymetrix, Inc., USA), and in-vitro transcription performed with the GeneChip IVT Labeling Kit (Affymetrix, Inc., USA). The biotin-labeled IVT-RNA was hybridized to HG-U133A-2 arrays (Affymetrix, Inc., USA) containing 14,500 well-annotated human genes, washed in a GeneChip Fluidics Station 450 and scanned according to the manufacturer's protocol using GeneArray-™ scanner G2500A (Hewlett Packard, USA).

2.2. Data Analysis

Data analysis was performed using Partek Genomics Solution software (www.partek.com). Expression values were computed from raw CEL files by applying the Robust Multi-Chip Average (RMA) background correction algorithm. RMA correction included: 1) values background correction; 2) quintile normalization; 3) log 2 transformation; and 4) median polish summarization. ANOVA analysis was applied to compare PBMC gene expression after one and six months of LAQ/placebo treatment as compared with baseline. Age, gender and batch effects were regarded as confounders in the ANOVA model. Genes that significantly changed in the placebo treated patients as compared to baseline were excluded from further analysis to yield only genes exclusively associated with LAQ effects. MIGs were defined as those that differentiated between groups with p<0.01. Gene functional annotation, enrichment and pathway analyses to identify the involved biological pathways were performed by Ingenuity Pathways Analysis software (www.ingenuity.com). All p values were applied for multiple testing corrections using False Discovery Rate (FDR) method with a cut off at p*0.05.

2.3. Verification by Western Blot

Protein fractions were purified from PBMC of 5 patients at baseline and after six months of LAQ treatment. Proteins were extracted from TRIZOL fractions and solubilized following the method reported by Hummon et al., 2007 (Hummon et al., 2007). Equal amounts of proteins were resolved on 10% SDS-PAGE and transferred onto nitrocellulose membranes (Invitrogen kit) for subsequent immune-blotting with antibodies specific for TGFb, ITGB1, CXCR1 and alpha Tubulin (Santa Cruz Biotechnology, Inc Santa Cruz, Calif., USA). Blots were analyzed by standard chemi-luminescence (Supersignal Kit, Pierce, Rockford, Ill., USA) and visualization was done by ChemiDoc™ XRS System (Bio-Rad).

3. Results

Samples were obtained from 25 RRMS patients, age 38.0±2.0 years, female/male ratio 16/9. The LAQ treatment arm consists of 13 patients, female/male ratio 8/5, age 38.8±2.3 years and the placebo arm consists of 12 patients, female/male ratio 8/4, age 37.2±3.4 years.

LAQ induced a differential gene expression of 354 MIGs after one month of treatment and the number of MIGs increased to 1562 after six months (Table 6 and 7).

The majority of genes that significantly changed expression under LAQ treatment at one and six months of treatment were down regulated (98% and 99%, respectively).

3.1. Biological Pathways Associated with LAQ Treatment: Down-Regulation of TGFb and NFkB Signaling and Pro Inflammatory Cytokines

Functional enrichment analysis of 354 MIGs after one month of LAQ treatment disclosed the suppression of molecules associated with different mechanisms of inflammatory response and cellular movement presented in Table 5. Indeed, analysis of the 1562 MIGs after six months showed growing number of genes involved with these mechanisms. Of the significantly suppressed pathways, the TGFb superfamily signaling (Table 5, p=3.2*10⁻³) was suppressed after one as well as after six months of LAQ treatment (p=4.32*10⁻²).

TABLE 5 Major biological pathways and functions affected by LAQ treatment After one month of treatment n = 345 After six months of treatment n = 1562 No. of No. of Function Pathway genes p-value Function Pathway genes p-value Inflammatory TGFb 10 3.2 × 10⁻³ Inflammatory TGFb 14 4.3 × 10⁻² response signaling response signaling IL-12 11 3.2 × 10⁻³ signaling Cellular Adhesion & 9 1.2 × 10⁻³ Cellular Invasion of 120 5.6 × 10⁻⁵ movement migration of movement cells phagocytes Chemotaxis of 4 6.0 × 10⁻³ Adhesion 119 2.4 × 10⁻⁵ Neutrophils of cells Transmigration 8 1.9 × 10⁻³ Leukocyte 29 9.4 × 10⁻³ of leukocytes extravasation signaling

Downregulation of the TGFb signaling pathway after one month of LAQ treatment was evident by suppression of TGFb and LTBP1 genes, the latter regulates secretion and activation of TGFb and thus promoting a feedback mechanism. After six months, down-regulation of additional TGFb superfamily related genes like BMP2/4/7, MIS, Type II BMP receptor, Smad14/5/6/8, TCF20, TCF2, Runx2 and the downstream ITGB1 was demonstrated (FIG. 9B).

Also, LAQ induced down-regulation of LFA-1 and VLA-4 expression that act with ITGB1 in adhesion of immune cells. The suppression of TGFb pathway after six months of LAQ treatment was accompanied by down regulation of IL-12 signaling pathway (p=6.2*10⁻³) and a wide range of other pro-inflammatory cytokines such as IL-9/11/12/20/36, TNFRSF11A/B, IFNA4/8/10/17, and also the receptors for IL-5/13/20/22 (p=3*10⁻³ to 9*10⁻³).

The molecular signature of LAQ after 6 months was also characterized by suppression of NFkB signaling as demonstrated by down regulation of members of the NFkB signaling that play a role in inflammation including IL-1, IL-1R and IKKg (FIG. 9B).

Altogether, these findings figure out a comprehensive suppression of pro-inflammatory cytokines and the key TGFb and NFkB pathways following six months of LAQ treatment. In view of the early down-regulation of TGFb at one month that precede the down-regulation of genes of pro-inflammatory cytokines, the inventors suggest that TGFb signaling precedes the suppression of inflammatory cytokines and that LAQ down regulates cytokine expression via suppression of TGFb.

Only five LAQ responsive MIGs were upregulated with the common three genes SASH1, FUCA1 and XYLT1 at one and six months. Although none of them integrated in firmed canonical pathway, overexpression of SASH1 and FUCA1 is associated with the inhibition of growth, proliferation, and invasion of cells (Meng et al., 2013).

3.2. LAQ Down-Regulates Expression of Migration, Adhesion and Leukocyte Extravasations Genes

Differential expression of cellular movement and migration were observed already after one month of LAQ treatment (p=3.49*10⁻⁴). These included down-regulation of genes associated with adhesion and migration of phagocytes (p=1.2*10⁻³), chemotaxis of neutrophils (p=6*10⁻³) and transmigration of leukocytes (p=1.9*10⁻³). Genes associated with cell movement and suppressed by LAQ were P selectin that is involved in the initial stage of adhesion and the integrin family members like ITGB1/3/5/6/8 and ITGA8 involved in later steps of adhesion and locomotion during leukocytes extravasation (p-value 1.72*10⁻³ to 5.5*10⁻³).

The suppressing effects of LAQ on cell adhesion and integrin expression were further enhanced after six months of treatment as was evident by down regulation of genes associated with cellular movement mechanisms (p value 3.15*10⁻⁶ to 3.79*10⁻³) including cell invasion (p=5.6*10⁻⁵), adhesion (p=2.4*10⁻⁵) and leukocyte extravasation (p=9.4*10⁻³), (Table 5, supra).

Similar to the observed effects of suppressed expression of the integrin family members after one month of treatment, suppression was even more evident after six months of LAQ treatment including integrin genes like ITGB/5/6/8, ITGA8, ITGB8, and ITGA2B (p value 9.84*10⁻⁴ to 1.1*10⁻³). In addition, suppression of inflammatory related chemokines like CCL19 and chemokine receptor CXCR1/2 was also demonstrated (p=6.79*10⁻³). Moreover, LAQ down-regulated a range of metalloproteinase family members such as MMP16/24/26/28, and ADAM12/18/22 that play a role during extravasation (p=4.95*10⁻⁴ to 1.26*10⁻³).

3.3. Verification of Key Genes Associated with LAQ Induced Molecular Pathways

The verification experiments performed by Western Blot analysis show significant down-regulation of key genes associated with most significantly affected biological mechanisms of LAQ. The TGFb protein following six months of LAQ treatment was suppressed by 69.0% (p=0.009) as could be seen from quantification of bands intensities (FIG. 10A). Accordingly, FIG. 10B shows down regulation of ITGB1, a common subunit of different integrin receptors by 40% (p=0.03) and of CXCR1 by 24.7% (p=0.014) (FIG. 10C).

4. Discussion

The results demonstrate that the most significant effect of LAQ is induction of suppression of inflammatory response via TGFb and NFkB pathways, as well as decrease in cell movement processes including adhesion, migration and leukocyte extravasation.

The inventors observed down-regulation of signaling pathways involving integrins, chemokines and metalloproteinases accompanied by repression of pro-inflammatory cytokines. These effects were observed in RRMS patients treated over six months-period as compared with baseline. Notably, the suppressive effects of LAQ are already detected as early as one month after initiation of treatment although to a lesser extent, suggesting a time-dependent treatment effect.

The pivotal function of TGFb in the immune system is anti-inflammatory, to maintain tolerance via regulation of lymphocyte proliferation, differentiation and survival. However, in MS it has been shown that in addition to its anti-inflammatory role, TGFb paradoxically can act as pro-inflammatory factor involved in the genesis of the pathogenic EAE-inducing TH17 cells. Thus, deletion of the TGFb gene from activated T cells, is known to abrogate Th17 cell differentiation, resulting in almost complete protection from EAE, confirming TGFb proinflammatory potential (Oh and Li, 2013). In the same process of events, TGFb is involved in stimulation of inflammatory cells adhesion, migration and extravasation, and could promote penetration of auto-aggressive lymphocytes to the central nervous system (CNS) (Bartolome et al., 2003; Brill et al., 2001). TGFb is also known to regulate the expression of IL-9 (Takami et al, 2012) and IL-22 (Sanjabi et al., 2009), thereby enhancing the expression of molecules associated with inflammation. TGFb itself can be activated by IL-1 (Luo et al., 2009), however IL-1 was also found to be suppressed in LAQ gene expression signature.

In accordance with observations linking TGFb with inflammatory process, the suppression of TGFb and members of the TGFb pathway by LAQ could result in beneficial reduction of active inflammation in MS. The suppression of TGFb signaling by LAQ corroborates with previous publications in which LAQ suppresses MAP3K7 (TAK1) that is strong positive regulator of cellular proliferation mediated by TGFb activation in CD14+ cells (Gurevich et al., 2010; Wan et al., 2006).

The inventors have demonstrated the suppressed expression of large number of cell adhesion and cell movement molecules involved in different stages of leukocytes extravasation under LAQ treatment. The ability of inflammatory cells to move from the periphery to the CNS is a crucial multistep process in MS with the following components down regulated by LAQ: a) Selectin P and IL-8R (CXCR1/2), that mediate rolling and the initial leukocyte-endothelial interactions; b) VLA-4, LFA-1, ITGA2/8, and ITGB1-6 integrins that mediate leukocyte adhesion and transmigration; c) chemokines and chemokine receptors for integrin activation like CCL19 that is responsible for leukocyte arrest and transmigration, and IL-8 receptor (CXCR1/2). These genes are well fitted with the steps of rolling, activation, adhesion, locomotion protrusion and transmigration of immune cells during extravasation to the CNS (as shown in FIG. 8C). Taken together, findings of the present study suggest that LAQ acts through inhibition of immune cells movement, adhesion and transmigration, thereby reducing the migratory capacity of active inflammatory cells trough the blood brain barrier (BBB). The supression of these cell migration functions corroborate with previously reported effects of LAQ- to induce down regulation of various cytokines and integrins such as IL-12, IL-13, IL-17, IFN-γ, TNF-α and VLA-4-mediated adhesiveness resulting in interference with migratory capacity of T cells in EAE (Brück and Wegner, 2011; Jadidi-Niaragh et al., 2011; Wegner et al., 2010).

Similarly, in MS patients, the inventors have demonstrated that LAQ down-regulates IL-1, IL-1R, IL12 and IKKg genes associated with pro-inflammatory NFkB pathway. The suppression of NFkB mechanism by LAQ was also demonstrated in an in-vitro study on PBMC obtained from MS patients (Gurevich et al., 2010) and in astrocytes following LAQ treatment in cuprizone-induced demyelination model (Bruck et al., 2012). NFkB signaling mediates IL-12 activation in macrophages (Murphy et al., 1995). The inventors have determined that LAQ may suppress both IL1 and IL2 dependent inflammation via down regulation of NFkB signaling.

These inflammation counteracting effects of LAQ could be the molecular basis of the positive imaging effect of LAQ in the ALLEGRO trial (Comi et al., 2012; Filippi et al., 2014).

Only 5 genes were up-regulated by LAQ; three of these up regulated genes were up-regulated already after one month of treatment with sustained effect at 6 months; Sash1 and FUCA1 are involved in suppression of proliferation while XYLT catalyzes the biosynthesis of glycosaminoglycan and its high activity was reported in patients with impaired BBB (Ponighaus et al., 2007). After six months of treatment, another growth inhibitor gene PID1 was overexpressed, confirming the suppression of proliferation of CD8+ cells by LAQ (Gurevich et al., 2010).

The inventors believe this to be the first study that characterizes LAQ induced transcriptional profile of RRMS patients demonstrating LAQ suppression of inflammatory cytokines and leukocytes extravasation either directly or via suppression of TGFb superfamily and NFkB signaling, thereby contributing to amelioration of the disease process of MS.

TABLE 6 p-value Fold-Change Column ID Gene Symbol Gene Title (1.0 vs. 0.0) (1.0 vs. 0.0) 202380_s_at NKTR natural killer-tumor 3.20E−05 −1.12256 recognition sequence 215673_at TEF thyrotrophic embryonic 4.00E−05 −1.16076 factor 219414_at CLSTN2 calsyntenin 2 4.51E−05 −1.12845 220099_s_at LUC7L2 LUC7-like 2 9.60E−05 −1.15527 (S. cerevisiae) 215492_x_at PTCRA pre T-cell antigen 0.000172567 −1.52614 receptor alpha 207426_s_at TNFSF4 tumor necrosis factor 0.000172751 −1.7061 (ligand) superfamily, member 4 205030_at FABP7 fatty acid binding 0.000176697 −1.17613 protein 7, brain 220205_at TPTE transmembrane 0.000181472 −1.15822 phosphatase with tensin homology 208782_at FSTL1 follistatin-like 1 0.00019072 −1.69352 201071_x_at SF3B1 splicing factor 3b, 0.000259586 −1.0879 subunit 1, 155 kDa 207198_s_at LIMS1 LIM and senescent cell 0.000294426 −1.44487 antigen-like domains 1 206757_at PDE5A phosphodiesterase 5A, 0.000306957 −1.213 cGMP-specific 209045_at XPNPEP1 X-prolyl aminopeptidase 0.000348404 −1.19661 (aminopeptidase P) 1, soluble 48031_r_at C5orf4 chromosome 5 open 0.000363815 −1.51923 reading frame 4 220921_at SPANXB1 /// SPANX family, member 0.000369349 −1.16871 SPANXB2 /// B1 /// SPANX family, SPANXF1 member B2 /// SPANX family, member F1 202729_s_at LTBP1 latent transforming 0.000383136 −1.71014 growth factor beta binding protein 1 213953_at KRT20 keratin 20 0.000398517 −1.13707 214146_s_at PPBP pro-platelet basic 0.000468646 −1.45959 protein (chemokine (C- X-C motif) ligand 7) 214013_s_at TBC1D1 TBC1 (tre-2/USP6, 0.000514065 −1.21818 BUB2, cdc16) domain family, member 1 219388_at GRHL2 grainyhead-like 2 0.000551908 −1.13133 (Drosophila) 220751_s_at C5orf4 chromosome 5 open 0.000640518 −1.96738 reading frame 4 211252_x_at PTCRA pre T-cell antigen 0.000650924 −1.38911 receptor alpha 206390_x_at PF4 platelet factor 4 0.00069054 −1.76355 213666_at SEPT6 septin 6 0.000693884 −1.13383 212942_s_at KIAA1199 KIAA1199 0.000714369 −1.12102 203016_s_at SSX2IP synovial sarcoma, X 0.000739497 −1.36137 breakpoint 2 interacting protein 206116_s_at TPM1 tropomyosin 1 (alpha) 0.00075228 −1.49626 221556_at CDC14B CDC14 cell division 0.000762595 −1.48795 cycle 14 homolog B (S. cerevisiae) 221518_s_at USP47 ubiquitin specific 0.000785063 −1.07574 peptidase 47 205612_at MMRN1 multimerin 1 0.000786871 −1.37634 202468_s_at CTNNAL1 catenin (cadherin- 0.000828338 −1.41611 associated protein), alpha-like 1 210357_s_at SMOX spermine oxidase 0.000848049 −1.40727 207206_s_at ALOX12 arachidonate 12- 0.000911895 −1.83581 lipoxygenase 210661_at GLRA3 glycine receptor, alpha 3 0.000946566 −1.15569 209301_at CA2 carbonic anhydrase II 0.000964786 −1.68995 211555_s_at GUCY1B3 guanylate cyclase 1, 0.00100045 −1.61803 soluble, beta 3 207934_at RFPL1 ret finger protein-like 1 0.00102558 −1.14458 220496_at CLEC1B C-type lectin domain 0.00102643 −2.04495 family 1, member B 204115_at GNG11 guanine nucleotide 0.00102931 −1.67885 binding protein (G protein), gamma 11 220558_x_at TSPAN32 tetraspanin 32 0.00108103 −1.15615 204319_s_at RGS10 regulator of G-protein 0.00108604 −1.27188 signaling 10 201615_x_at CALD1 caldesmon 1 0.00112603 −1.44221 203680_at PRKAR2B protein kinase, cAMP- 0.00119671 −1.87579 dependent, regulatory, type II, beta 206153_at CYP4F11 cytochrome P450, 0.00121638 −1.09486 family 4, subfamily F, polypeptide 11 220810_at CLCA3P chloride channel 0.00123986 −1.14123 accessory 3 (pseudogene) 40020_at CELSR3 cadherin, EGF LAG 0.00127162 −1.12078 seven-pass G-type receptor 3 (flamingo homolog, Drosophila) 208022_s_at CDC14B CDC14 cell division 0.00133236 −1.4133 cycle 14 homolog B (S. cerevisiae) 210987_x_at TPM1 tropomyosin 1 (alpha) 0.00135846 −1.44653 214298_x_at SEPT6 septin 6 0.00137756 −1.13328 207119_at PRKG1 protein kinase, cGMP- 0.00141929 −1.18474 dependent, type I 210734_x_at MAX MYC associated factor X 0.00142961 −1.28358 209689_at CCDC93 coiled-coil domain 0.0014704 −1.13336 containing 93 214749_s_at ARMCX6 /// armadillo repeat 0.00149785 −1.17832 LOC653354 containing, X-linked 6 /// similar to armadillo repeat containi 214023_x_at TUBB2B tubulin, beta 2B 0.00153776 −1.15934 208583_x_at HIST1H2AJ histone cluster 1, H2aj 0.00154449 −1.27798 205442_at MFAP3L microfibrillar-associated 0.0015663 −1.85392 protein 3-like 212687_at LIMS1 LIM and senescent cell 0.00160765 −1.3332 antigen-like domains 1 211871_x_at GNB5 guanine nucleotide 0.00163175 −1.15867 binding protein (G protein), beta 5 204793_at GPRASP1 G protein-coupled 0.00165477 −1.16021 receptor associated sorting protein 1 201680_x_at SRRT serrate RNA, effector 0.00172271 −1.11791 molecule homolog (Arabidopsis) 211837_s_at PTCRA pre T-cell antigen 0.00177798 −1.27392 receptor alpha 219476_at C1orf116 chromosome 1 open 0.00181581 −1.22156 reading frame 116 201178_at FBXO7 F-box protein 7 0.00186196 −1.13506 203966_s_at PPM1A protein phosphatase 1A 0.00188506 −1.18222 (formerly 2C), magnesium-dependent, alpha isoform 203817_at GUCY1B3 guanylate cyclase 1, 0.00189066 −1.72974 soluble, beta 3 201125_s_at ITGB5 integrin, beta 5 0.00191776 −1.71341 201905_s_at CTDSPL CTD (carboxy-terminal 0.00197783 −1.46779 domain, RNA polymerase II, polypeptide A) small phosphatas 200780_x_at GNAS GNAS complex locus 0.00198667 −1.15838 203819_s_at IGF2BP3 insulin-like growth 0.0019919 −1.71954 factor 2 mRNA binding protein 3 210986_s_at TPM1 tropomyosin 1 (alpha) 0.00199934 −1.55544 209806_at HIST1H2BK histone cluster 1, H2bk 0.00202655 −1.41838 210684_s_at DLG4 discs, large homolog 4 0.00202851 −1.18659 (Drosophila) 222157_s_at WDR48 WD repeat domain 48 0.00207579 −1.10297 212077_at CALD1 caldesmon 1 0.00217742 −1.89576 214839_at LOC157627 hypothetical 0.00223956 1.32598 LOC157627 207124_s_at GNB5 guanine nucleotide 0.00230176 −1.1663 binding protein (G protein), beta 5 205514_at ZNF415 zinc finger protein 415 0.00231529 −1.15423 206049_at SELP selectin P (granule 0.00232343 −1.64193 membrane protein 140 kDa, antigen CD62) 206414_s_at ASAP2 ArfGAP with SH3 0.00233503 −1.77303 domain, ankyrin repeat and PH domain 2 218613_at PSD3 pleckstrin and Sec7 0.00234479 −1.25828 domain containing 3 200981_x_at GNAS GNAS complex locus 0.00238211 −1.1585 211945_s_at ITGB1 integrin, beta 1 0.00241794 −1.17026 (fibronectin receptor, beta polypeptide, antigen CD29 includes 219926_at POPDC3 popeye domain 0.00243065 −1.1575 containing 3 204081_at NRGN neurogranin (protein 0.00243424 −1.60366 kinase C substrate, RC3) 205730_s_at ABLIM3 actin binding LIM 0.00246133 −1.54178 protein family, member 3 213725_x_at XYLT1 xylosyltransferase I 0.00253677 1.31402 210702_s_at PTGIS prostaglandin I2 0.00258067 −1.09522 (prostacyclin) synthase 215139_at ARHGEF10 Rho guanine nucleotide 0.00258297 −1.17563 exchange factor (GEF) 10 205463_s_at PDGFA platelet-derived growth 0.00261003 −1.53627 factor alpha polypeptide 204628_s_at ITGB3 integrin, beta 3 (platelet 0.00264187 −1.57906 glycoprotein IIIa, antigen CD61) 201121_s_at PGRMC1 progesterone receptor 0.00266076 −1.44314 membrane component 1 215071_s_at HIST1H2AC histone cluster 1, H2ac 0.00271978 −1.62836 212273_x_at GNAS GNAS complex locus 0.00273624 −1.15606 204482_at CLDN5 claudin 5 0.00276964 −1.36386 210493_s_at MFAP3L microfibrillar-associated 0.0027754 −1.46358 protein 3-like 201120_s_at PGRMC1 progesterone receptor 0.0027801 −1.43219 membrane component 1 202423_at MYST3 MYST histone 0.00280673 −1.07974 acetyltransferase (monocytic leukemia) 3 200722_s_at CAPRIN1 cell cycle associated 0.00288696 −1.15665 protein 1 201617_x_at CALD1 caldesmon 1 0.0028931 −1.32568 218751_s_at FBXW7 F-box and WD repeat 0.00289921 −1.11226 domain containing 7 209839_at DNM3 dynamin 3 0.00294256 −1.79997 211190_x_at CD84 CD84 molecule 0.0029693 −1.16616 202127_at PRPF4B PRP4 pre-mRNA 0.00299632 −1.13501 processing factor 4 homolog B (yeast) 202280_at — — 0.00302852 −1.15673 212031_at RBM25 RNA binding motif 0.00302972 −1.10451 protein 25 204042_at WASF3 WAS protein family, 0.00304453 −1.60611 member 3 208406_s_at GRAP2 GRB2-related adaptor 0.0030481 −1.39443 protein 2 200665_s_at SPARC secreted protein, acidic, 0.00304843 −1.77594 cysteine-rich (osteonectin) 206283_s_at TAL1 T-cell acute 0.00307052 −1.75245 lymphocytic leukemia 1 218407_x_at NENF neuron derived 0.0030954 −1.14125 neurotrophic factor 206698_at XK X-linked Kx blood 0.00309645 −1.88028 group (McLeod syndrome) 207389_at GP1BA glycoprotein Ib 0.00310255 −1.54848 (platelet), alpha polypeptide 215240_at ITGB3 integrin, beta 3 (platelet 0.00313548 −1.58871 glycoprotein IIIa, antigen CD61) 217456_x_at HLA-E major histocompatibility 0.00314152 −1.06184 complex, class I, E 207421_at CA5A carbonic anhydrase VA, 0.00315794 −1.24281 mitochondrial 220037_s_at LYVE1 lymphatic vessel 0.00316412 −1.13941 endothelial hyaluronan receptor 1 203085_s_at TGFB1 transforming growth 0.00316654 −1.24041 factor, beta 1 201736_s_at MARCH6 membrane-associated 0.00323685 −1.13929 ring finger (C3HC4) 6 206964_at NAT8B N-acetyltransferase 8B 0.00333385 −1.74593 (GCN5-related, putative, gene/pseudogene) 215047_at TRIM58 tripartite motif- 0.00338565 −1.77665 containing 58 211421_s_at RET ret proto-oncogene 0.00341726 −1.22099 218711_s_at SDPR serum deprivation 0.00342263 −1.66157 response (phosphatidylserine binding protein) 336_at TBXA2R thromboxane A2 0.00343156 −1.43266 receptor 200929_at TMED10 transmembrane emp24- 0.00344518 −1.09881 like trafficking protein 10 (yeast) 209871_s_at APBA2 amyloid beta (A4) 0.00349415 −1.16326 precursor protein- binding, family A, member 2 201058_s_at MYL9 myosin, light chain 9, 0.003504 −1.74013 regulatory 207846_at POU1F1 POU class 1 homeobox 1 0.00351318 −1.09086 208579_x_at H2BFS /// H2B histone family, 0.00351435 −1.48066 HIST1H2BK member S /// histone cluster 1, H2bk 220759_at FAM12B family with sequence 0.0035357 −1.1468 similarity 12, member B (epididymal) 200931_s_at VCL vinculin 0.00355492 −1.40602 217595_at GSPT1 G1 to S phase transition 1 0.00359115 −1.11645 204704_s_at ALDOB aldolase B, fructose- 0.00362444 −1.11912 bisphosphate 207856_s_at LOC150776 /// sphingomyelin 0.00363765 −1.0672 SMPD4 phosphodiesterase 4, neutral membrane pseudogene /// sphingomyelin 218928_s_at SLC37A1 solute carrier family 37 0.00364173 −1.12611 (glycerol-3-phosphate transporter), member 1 212667_at SPARC secreted protein, acidic, 0.00365945 −1.72956 cysteine-rich (osteonectin) 214548_x_at GNAS GNAS complex locus 0.00366147 −1.15948 221392_at TAS2R4 taste receptor, type 2, 0.00366806 −1.20308 member 4 200622_x_at CALM3 calmodulin 3 0.00368294 −1.2967 (phosphorylase kinase, delta) 212178_s_at POM121 /// POM121 membrane 0.00369813 −1.09132 POM121C glycoprotein (rat) /// POM121 membrane glycoprotein C 215993_at — — 0.00369964 −1.07521 215655_at GRIK2 Glutamate receptor, 0.00371565 −1.12171 ionotropic, kainate 2 218468_s_at GREM1 gremlin 1, cysteine knot 0.00374196 −1.11604 superfamily, homolog (Xenopus laevis) 205388_at TNNC2 troponin C type 2 (fast) 0.00376489 −1.21183 207750_at EPS15L2 epidermal growth factor 0.00376694 −1.1441 receptor pathway substrate 15-like 2 212573_at ENDOD1 endonuclease domain 0.00376788 −1.29339 containing 1 210270_at RGS6 regulator of G-protein 0.00377039 −1.25086 signaling 6 211185_s_at SF3B1 splicing factor 3b, 0.00378516 −1.0809 subunit 1, 155 kDa 205347_s_at TMSB15A thymosin beta 15a 0.0038153 −1.11916 205383_s_at ZBTB20 zinc finger and BTB 0.00387924 −1.13702 domain containing 20 214046_at FUT9 fucosyltransferase 9 0.00390947 −1.12688 (alpha (1,3) fucosyltransferase) 212062_at ATP9A ATPase, class II, type 9A 0.00394326 −1.44071 214974_x_at CXCL5 chemokine (C-X-C 0.00401473 −1.73103 motif) ligand 5 209331_s_at MAX MYC associated factor X 0.00402443 −1.24493 215306_at — — 0.00405048 −1.22628 214542_x_at HIST1H2AI histone cluster 1, H2ai 0.0040542 −1.2842 211948_x_at BAT2D1 BAT2 domain 0.00405795 −1.08274 containing 1 202123_s_at ABL1 c-abl oncogene 1, 0.00406538 −1.10234 receptor tyrosine kinase 211546_x_at SNCA synuclein, alpha (non 0.00409573 −1.35092 A4 component of amyloid precursor) 208501_at GFI1B growth factor 0.00411391 −1.55771 independent 1B transcription repressor 200661_at CTSA cathepsin A 0.00411941 −1.29244 215820_x_at SNX13 sorting nexin 13 0.00412146 −1.18742 204486_at — — 0.00413941 −1.18519 201529_s_at RPA1 replication protein A1, 0.00422086 −1.26569 70 kDa 214752_x_at FLNA filamin A, alpha 0.00426746 −1.14045 208453_s_at XPNPEP1 X-prolyl aminopeptidase 0.00430113 −1.19059 (aminopeptidase P) 1, soluble 203086_at KIF2A kinesin heavy chain 0.00434355 −1.27703 member 2A 214631_at ZBTB33 zinc finger and BTB 0.0043722 −1.13452 domain containing 33 202728_s_at LTBP1 latent transforming 0.00437355 −1.47988 growth factor beta binding protein 1 208776_at PSMD11 proteasome (prosome, 0.00439519 −1.12238 macropain) 26S subunit, non-ATPase, 11 212751_at UBE2N ubiquitin-conjugating 0.00441391 −1.10218 enzyme E2N (UBC13 homolog, yeast) 204437_s_at FOLR1 folate receptor 1 (adult) 0.0044397 −1.21956 215111_s_at TSC22D1 TSC22 domain family, 0.00446803 −1.61432 member 1 217816_s_at PCNP PEST proteolytic signal 0.00447658 −1.13528 containing nuclear protein 205165_at CELSR3 cadherin, EGF LAG 0.00452773 −1.16533 seven-pass G-type receptor 3 (flamingo homolog, Drosophila) 206465_at ACSBG1 acyl-CoA synthetase 0.004567 −1.54878 bubblegum family member 1 208924_at RNF11 ring finger protein 11 0.00458077 −1.38056 206941_x_at SEMA3E sema domain, 0.00459381 −1.14106 immunoglobulin domain (Ig), short basic domain, secreted, (semaphor 210075_at MARCH2 membrane-associated 0.00459416 −1.3917 ring finger (C3HC4) 2 220186_s_at PCDH24 protocadherin 24 0.00460173 −1.12071 201480_s_at SUPT5H suppressor of Ty 5 0.00461915 −1.10301 homolog (S. cerevisiae) 200904_at HLA-E major histocompatibility 0.00463895 −1.12592 complex, class I, E 206254_at EGF epidermal growth factor 0.00468322 −1.73397 (beta-urogastrone) 214459_x_at HLA-C major histocompatibility 0.00473524 −1.06284 complex, class I, C 200859_x_at FLNA filamin A, alpha 0.00474228 −1.15462 201938_at CDK2AP1 cyclin-dependent kinase 0.0047647 −1.36598 2 associated protein 1 202378_s_at LEPROT leptin receptor 0.00479261 −1.26088 overlapping transcript 219710_at SH3TC2 SH3 domain and 0.00480083 −1.22839 tetratricopeptide repeats 2 212242_at TUBA4A tubulin, alpha 4a 0.00489677 −1.25565 213511_s_at MTMR1 myotubularin related 0.004902 −1.09827 protein 1 220109_at TF transferrin 0.00492572 −1.12186 217705_at PRKD1 protein kinase D1 0.00494361 −1.08153 208753_s_at NAP1L1 nucleosome assembly 0.00495688 −1.22128 protein 1-like 1 201280_s_at DAB2 disabled homolog 2, 0.00497063 −1.64395 mitogen-responsive phosphoprotein (Drosophila) 202838_at FUCA1 fucosidase, alpha-L-1, 0.00499711 1.56419 tissue 205426_s_at HIP1 huntingtin interacting 0.00499868 −1.14213 protein 1 211154_at THPO thrombopoietin 0.00502652 −1.11697 214577_at MAP1B micro tubule-associated 0.00512459 −1.14783 protein 1B 37966_at PARVB parvin, beta 0.00513617 −1.45109 209767_s_at GP1BB /// glycoprotein Ib 0.00515773 −1.47137 SEPT5 (platelet), beta polypeptide /// septin 5 40687_at GJA4 gap junction protein, 0.00516689 −1.14585 alpha 4, 37 kDa 216463_at — — 0.00517514 −1.14524 205128_x_at PTGS1 prostaglandin- 0.00517864 −1.54268 endoperoxide synthase 1 (prostaglandin G/H synthase and cyclooxyge 221942_s_at GUCY1A3 guanylate cyclase 1, 0.00526751 −1.70831 soluble, alpha 3 207156_at HIST1H2AG histone cluster 1, H2ag 0.0053042 −1.67358 211858_x_at GNAS GNAS complex locus 0.00533874 −1.13613 212692_s_at LRBA LPS-responsive vesicle 0.00540408 −1.1862 trafficking, beach and anchor containing 211728_s_at HYAL3 hyaluronoglucosaminidase 3 0.00545859 −1.16784 220336_s_at GP6 glycoprotein VI 0.00546958 −1.61325 (platelet) 217083_at IGHG1 Immunoglobulin heavy 0.00548613 −1.16387 constant gamma 1 (G1m marker) 208327_at CYP2A13 cytochrome P450, 0.00550711 −1.14862 family 2, subfamily A, polypeptide 13 221555_x_at CDC14B CDC 14 cell division 0.0055286 −1.35261 cycle 14 homolog B (S. cerevisiae) 211567_at — — 0.00553946 −1.12571 208403_x_at MAX MYC associated factor X 0.00557349 −1.29399 208989_s_at KDM2A lysine (K)-specific 0.00557809 −1.10556 demethylase 2A 201616_s_at CALD1 caldesmon 1 0.00558092 −1.48431 204993_at GNAZ guanine nucleotide 0.00558421 −1.47787 binding protein (G protein), alpha z polypeptide 221764_at C19orf22 chromosome 19 open 0.00558498 −1.1412 reading frame 22 206167_s_at ARHGAP6 Rho GTPase activating 0.0055881 −1.76822 protein 6 204627_s_at ITGB3 integrin, beta 3 (platelet 0.00559095 −1.9911 glycoprotein IIIa, antigen CD61) 200885_at RHOC ras homolog gene 0.00563494 −1.28435 family, member C 218117_at RBX1 ring-box 1 0.0056402 −1.1728 206655_s_at GP1BB /// glycoprotein Ib 0.00564505 −1.81428 SEPT5 (platelet), beta polypeptide /// septin 5 200844_s_at PRDX6 peroxiredoxin 6 0.00565286 −1.14511 216881_x_at PRB4 proline-rich protein 0.00566372 −1.11675 BstNI subfamily 4 213746_s_at FLNA filamin A, alpha 0.00567458 −1.16364 208490_x_at HIST1H2BF histone cluster 1, H2bf 0.00567635 −1.43467 219202_at RHBDF2 rhomboid 5 homolog 2 0.00568725 −1.12168 (Drosophila) 222382_x_at NUP205 nucleoporin 205 kDa 0.00571901 −1.14196 203998_s_at SYT1 synaptotagmin I 0.00575584 −1.13457 209826_at EGFL8 /// EGF-like-domain, 0.0058323 −1.1054 PPT2 multiple 8 /// palmitoyl- protein thioesterase 2 208601_s_at TUBB1 tubulin, beta 1 0.00591408 −1.84224 214958_s_at TMC6 transmembrane channel- 0.00592428 −1.12494 like 6 217335_at FLJ11292 hypothetical protein 0.00594468 −1.15949 FLJ11292 213864_s_at NAP1L1 nucleosome assembly 0.00597059 −1.13884 protein 1-like 1 203180_at ALDH1A3 aldehyde dehydrogenase 0.00600686 −1.16713 1 family, member A3 202332_at CSNK1E casein kinase 1, epsilon 0.00600712 −1.08867 210988_s_at PRUNE prune homolog 0.00603465 −1.30051 (Drosophila) 216896_at COL4A3 collagen, type IV, alpha 0.00603529 −1.14088 3 (Goodpasture antigen) 220847_x_at ZNF221 zinc finger protein 221 0.00606358 1.15477 208931_s_at ILF3 interleukin enhancer 0.00609592 −1.14798 binding factor 3, 90 kDa 221160_s_at CABP5 calcium binding protein 5 0.00612012 −1.56239 201528_at RPA1 replication protein A1, 0.00612054 −1.2309 70 kDa 208750_s_at ARF1 ADP-ribosylation factor 1 0.00615213 −1.10243 208523_x_at HIST1H2BI histone cluster 1, H2bi 0.00617675 −1.47477 215813_s_at PTGS1 prostaglandin- 0.00620004 −1.55575 endoperoxide synthase 1 (prostaglandin G/H synthase and cyclooxyge 214917_at PRKAA1 protein kinase, AMP- 0.00621432 −1.17283 activated, alpha 1 catalytic subunit 204000_at GNB5 guanine nucleotide 0.00623899 −1.19485 binding protein (G protein), beta 5 207046_at HIST2H4A /// histone cluster 2, H4a /// 0.00626313 −1.23715 HIST2H4B histone cluster 2, H4b 201885_s_at CYB5R3 cytochrome b5 0.0062861 −1.15347 reductase 3 221748_s_at TNS1 tensin 1 0.0062959 −1.4944 216513_at DCT dopachrome 0.00633287 −1.16456 tautomerase (dopachrome delta- isomerase, tyrosine- related protein 2) 204187_at GMPR guanosine 0.00636191 −1.47328 monophosphate reductase 220518_at ABI3BP ABI family, member 3 0.00645579 −1.13443 (NESH) binding protein 217673_x_at GNAS GNAS complex locus 0.00646359 −1.13184 213236_at SASH1 SAM and SH3 domain 0.0064869 1.90481 containing 1 205434_s_at AAK1 AP2 associated kinase 1 0.00656002 −1.0984 211982_x_at XPO6 exportin 6 0.00657111 −1.07265 210074_at CTSL2 cathepsin L2 0.00658045 −1.24334 219705_at QSER1 glutamine and serine 0.00662733 −1.17822 rich 1 208786_s_at MAP1LC3B microtubule-associated 0.00665976 −1.14821 protein 1 light chain 3 beta 209651_at TGFB1I1 transforming growth 0.00668902 −1.76594 factor beta 1 induced transcript 1 215122_at TBX6 T-box 6 0.00679541 −1.14526 206110_at — — 0.00681334 −1.79605 207745_at CABP2 calcium binding protein 2 0.00682426 −1.13079 211334_at MRE11A MRE11 meiotic 0.00687602 −1.12163 recombination 11 homolog A (S. cerevisiae) 202501_at MAPRE2 microtubule-associated 0.00688368 −1.12271 protein, RP/EB family, member 2 204328_at TMC6 transmembrane channel- 0.00689317 −1.08397 like 6 213598_at — — 0.00699509 −1.22087 205870_at BDKRB2 bradykinin receptor B2 0.00701629 −1.14085 211026_s_at MGLL monoglyceride lipase 0.00710106 −1.60334 219983_at HRASLS HRAS-like suppressor 0.00719792 −1.52976 213908_at WHAMML1 /// WAS protein homolog 0.00719896 −1.37039 WHAMML2 associated with actin, golgi membranes and microtubules-like 208792_s_at CLU clusterin 0.00721848 −1.79473 204597_x_at STC1 stanniocalcin 1 0.00723265 −1.14445 207963_at C6orf54 chromosome 6 open 0.00723289 −1.15074 reading frame 54 213046_at PABPN1 poly(A) binding protein, 0.00723382 −1.1431 nuclear 1 208690_s_at PDLIM1 PDZ and LIM domain 1 0.00723389 −1.321 208791_at CLU clusterin 0.00725265 −1.77614 209423_s_at PHF20 PHD finger protein 20 0.00725781 −1.14876 221746_at UBL4A ubiquitin-like 4A 0.00726803 −1.2092 212742_at RNF115 ring finger protein 115 0.00727752 −1.09141 205221_at HGD homogentisate 1,2- 0.00729169 −1.52962 dioxygenase (homogentisate oxidase) 214369_s_at RASGRP2 RAS guanyl releasing 0.00738935 −1.10618 protein 2 (calcium and DAG-regulated) 210183_x_at PNN pinin, desmosome 0.00742741 −1.10331 associated protein 207799_x_at — — 0.00743344 −1.20384 217928_s_at SAPS3 SAPS domain family, 0.00749046 −1.10225 member 3 213431_x_at SFI1 Sfi1 homolog, spindle 0.00750358 −1.06935 assembly associated (yeast) 211059_s_at GOLGA2 golgi autoantigen, 0.00750762 −1.14379 golgin subfamily a, 2 202708_s_at HIST2H2BE histone cluster 2, H2be 0.00757968 −1.54991 222121_at SGEF Src homology 3 domain- 0.00760512 −1.1164 containing guanine nucleotide exchange factor 215653_at — — 0.00760953 −1.11511 201124_at ITGB5 integrin, beta 5 0.0076181 −1.25169 214308_s_at HGD homogentisate 1,2- 0.00764686 −1.64821 dioxygenase (homogentisate oxidase) 217912_at DUS1L dihydrouridine synthase 0.00767399 −1.08336 1-like (S. cerevisiae) 202974_at MPP1 membrane protein, 0.00775127 −1.36968 palmitoylated 1, 55 kDa 200905_x_at HLA-E major histocompatibility 0.00775135 −1.07063 complex, class I, E 216261_at ITGB3 integrin, beta 3 (platelet 0.0077566 −1.37764 glycoprotein IIIa, antigen CD61) 206204_at GRB14 growth factor receptor- 0.00781703 −1.79964 bound protein 14 203414_at MMD monocyte to 0.00782001 −1.41852 macrophage differentiation- associated 219779_at ZFHX4 zinc finger homeobox 4 0.00782075 −1.16711 202573_at CSNK1G2 casein kinase 1, gamma 2 0.00784114 −1.11116 208527_x_at HIST1H2BE histone cluster 1, H2be 0.00788446 −1.41486 213306_at MPDZ multiple PDZ domain 0.00799342 −1.10219 protein 216231_s_at B2M beta-2-microglobulin 0.00809127 −1.05409 207554_x_at TBXA2R thromboxane A2 0.00813716 −1.28702 receptor 217963_s_at NGFRAP1 nerve growth factor 0.00815053 −1.41005 receptor (TNFRSF16) associated protein 1 201904_s_at CTDSPL CTD (carboxy-terminal 0.00815064 −1.51442 domain, RNA polymerase II, polypeptide A) small phosphatas 205754_at F2 coagulation factor II 0.00816234 −1.14373 (thrombin) 204466_s_at SNCA synuclein, alpha (non 0.0081789 −1.56209 A4 component of amyloid precursor) 201029_s_at CD99 CD99 molecule 0.00820335 −1.12753 202466_at POLS polymerase (DNA 0.00822683 −1.10075 directed) sigma 207550_at MPL myeloproliferative 0.00828883 −1.89086 leukemia virus oncogene 208506_at HIST1H3F histone cluster 1, H3f 0.0083864 −1.13083 202774_s_at SFRS8 splicing factor, 0.00842382 −1.09754 arginine/serine-rich 8 (suppressor-of-white- apricot homolog, Dr 208343_s_at NR5A2 nuclear receptor 0.00845048 −1.11703 subfamily 5, group A, member 2 202778_s_at ZMYM2 zinc finger, MYM-type 2 0.00850235 −1.12722 207523_at C6orf10 chromosome 6 open 0.00859283 −1.11067 reading frame 10 219503_s_at TMEM40 transmembrane protein 40 0.00859971 −1.45661 218704_at RNF43 ring finger protein 43 0.00873092 −1.14893 209586_s_at PRUNE prune homolog 0.00873312 −1.23705 (Drosophila) 211449_at MSH6 mutS homolog 6 0.00875942 −1.11398 (E. coli) 203896_s_at PLCB4 phospholipase C, beta 4 0.00876295 −1.13939 204629_at PARVB parvin, beta 0.00884733 −1.27543 216623_x_at TOX3 TOX high mobility 0.00885472 −1.09839 group box Family member 3 204196_x_at PKNOX1 PBX/knotted 1 0.00892223 −1.11739 homeobox 1 215101_s_at CXCL5 chemokine (C-X-C 0.00893221 −1.66669 motif) ligand 5 218243_at RUFY1 RUN and FYVE 0.00894778 −1.43684 containing 1 204467_s_at SNCA A4 component of 0.00896008 −1.47629 amyloid precursor) 219857_at C10orf81 chromosome 10 open 0.00897475 −1.18546 reading frame 81 216867_s_at PDGFA platelet-derived growth 0.00897825 −1.3116 factor alpha polypeptide 206779_s_at ASMT acetylserotonin O- 0.00905468 −1.13282 methyltransferase 214938_x_at HMGB1 high-mobility group box 1 0.00906415 −1.08357 220094_s_at CCDC90A coiled-coil domain 0.00907588 −1.32015 containing 90A 207808_s_at PROS1 protein S (alpha) 0.00911187 −1.96407 200833_s_at hCG_1757335 /// RAP1B, member of 0.00912774 −1.12905 RAP1B RAS oncogene family pseudogene /// RAP1B, member of RAS oncogen 206176_at BMP6 bone morphogenetic 0.00916216 −1.52992 protein 6 210360_s_at MTSS1 metastasis suppressor 1 0.00917743 −1.16565 211522_s_at GNRHR gonadotropin-releasing 0.00918361 −1.12079 hormone receptor 209840_s_at LRRN3 leucine rich repeat 0.00922884 1.86067 neuronal 3 214514_at MCM3AP minichromosome 0.00924948 −1.13224 maintenance complex component 3 associated protein 202620_s_at PLOD2 procollagen-lysine, 2- 0.00936232 −1.26035 oxoglutarate 5- dioxygenase 2 208752_x_at NAP1L1 nucleosome assembly 0.00940735 −1.13425 protein 1-like 1 202619_s_at PLOD2 procollagen-lysine, 2- 0.00942205 −1.28918 oxoglutarate 5- dioxygenase 2 207397_s_at HOXD13 homeobox D13 0.00958266 −1.11525 61297_at CASKIN2 CASK interacting 0.00961064 −1.11013 protein 2 213765_at MFAP5 microfibrillar associated 0.00964722 −1.09199 protein 5 207558_s_at PITX2 paired-like 0.00964956 −1.10328 homeodomain 2 207827_x_at SNCA synuclein, alpha (non 0.00976329 −1.35299 A4 component of amyloid precursor) 202555_s_at MYLK myosin light chain 0.00978872 −1.59189 kinase 212151_at PBX1 pre-B-cell leukemia 0.00982704 −1.5597 homeobox 1 200845_s_at PRDX6 peroxiredoxin 6 0.00986511 −1.2308 217736_s_at EIF2AK1 eukaryotic translation 0.00989935 −1.23452 initiation factor 2-alpha kinase 1 213828_x_at H3F3A /// H3 histone, family 3A /// 0.00991103 −1.09735 H3F3B /// H3 histone, family 3B LOC440926 (H3.3B) /// H3 histone, family 3 216625_at — — 0.00997586 −1.10058

TABLE 7 p-value Fold-Change Gene Symbol Gene Title (4.0 vs. 0.0) (4.0 vs. 0.0) TMEM158 transmembrane protein 158 0.001631 −1.88182 TRIM58 tripartite motif-containing 58 0.004607 −1.73605 FSTL1 follistatin-like 1 0.001763 −1.66003 SNCA synuclein, alpha (non A4 0.006379 −1.59767 component of amyloid precursor) ITGB5 Integrin, beta 5 0.00485 −1.5805 TNS1 tensin 1 0.003402 −1.53358 ATP1B1 ATPase, Na+/K+ transporting, 0.008818 −1.51106 beta 1 polypeptide C5orf4 chromosome 5 open reading 0.005208 −1.46004 frame 4 LRP12 low density lipoprotein-related 0.002832 −1.42261 protein 12 CTNNAL1 catenin (cadherin-associated 0.009018 −1.40804 protein), alpha-like 1 GEM GTP binding protein 0.002764 −1.40178 overexpressed in skeletal muscle KIAA1466 KIAA1466 gene 0.002973 −1.39035 ALDH1A2 aldehyde dehydrogenase 1 0.000677 −1.38981 family, member A2 MAP4K3 mitogen-activated protein 0.007221 −1.37714 kinase kinase kinase kinase 3 SNCA synuclein, alpha (non A4 0.007255 −1.37607 component of amyloid precursor) RAB6B RAB6B, member RAS 0.007576 −1.37568 oncogene family PSD3 pleckstrin and Sec7 domain 0.000178 −1.37423 containing 3 RIPK2 receptor-interacting serine- 0.008392 −1.36879 threonine kinase 2 RAMP3 receptor (G protein-coupled) 0.002203 −1.36845 activity modifying protein 3 PTCRA pre T-cell antigen receptor 0.003563 −1.35879 alpha CALD1 caldesmon 1 0.002914 −1.35604 CYP2E1 cytochrome P450, family 2, 0.001334 −1.35372 subfamily E, polypeptide 1 PSD3 pleckstrin and Sec7 domain 0.000673 −1.35294 containing 3 PDLIM7 PDZ and LIM domain 7 0.003532 −1.34658 (enigma) COBLL1 COBL-like 1 0.002662 −1.34562 FUT3 fucosyltransferase 3 2.63E−05 −1.34512 (galactoside 3(4)-L- fucosyltransferase, Lewis blood group) SMOX spermine oxidase 0.006872 −1.34018 TGM2 transglutaminase 2 (C 0.002055 −1.33815 polypeptide, protein-glutamine- gamma-glutamyltransferase) LRRC50 leucine rich repeat containing 50 0.004871 −1.33114 CST6 cystatin E/M 0.001427 −1.33016 OR7A17 olfactory receptor, family 7, 0.000118 −1.32853 subfamily A, member 17 C6orf145 chromosome 6 open reading 0.00109 −1.32816 frame 145 DLEU2 /// deleted in lymphocytic 0.009215 −1.32582 DLEU2L leukemia 2 (non-protein coding) /// deleted in lymphocytic leuke CPT2 carnitine palmitoyltransferase 2 0.002605 −1.32033 HGF hepatocyte growth factor 0.007517 −1.31941 (hepapoietin A; scatter factor) TNS1 tensin 1 0.002806 −1.31579 SPRY1 sprouty homolog 1, antagonist 0.004614 −1.30993 of FGF signaling (Drosophila) PLOD2 procollagen-lysine, 2- 0.007309 −1.30719 oxoglutarate 5-dioxygenase 2 CD80 CD80 molecule 0.008637 −1.30572 KYNU kynureninase (L-kynurenine 0.009541 −1.30549 hydrolase) BCAT1 branched chain 0.009502 −1.30486 aminotransferase 1, cytosolic NHLH1 nescient helix loop helix 1 0.00122 −1.30451 AHCTF1 AT hook containing 0.006984 −1.30418 transcription factor 1 HOXA10 homeobox A10 0.007051 −1.30259 MTMR3 myotubularin related protein 3 0.001598 −1.30189 — — 0.000939 −1.30069 VAC14 Vac14 homolog (S. cerevisiae) 2.51E−05 −1.29695 CLCF1 cardiotrophin-like cytokine 0.003153 −1.2966 factor 1 FGF5 fibroblast growth factor 5 0.001 −1.29505 TAL1 T-cell acute lymphocytic 0.000808 −1.29347 leukemia 1 SAMD14 sterile alpha motif domain 0.00157 −1.29276 containing 14 ELL2 elongation factor, RNA 0.006259 −1.29209 polymerase II, 2 CHN1 chimerin (chimaerin) 1 0.006634 −1.2914 SLC7A1 solute carrier family 7 (cationic 0.009963 −1.28978 amino acid transporter, y+ system), member 1 GRK5 G protein-coupled receptor 0.000218 −1.28944 kinase 5 PARD3 par-3 partitioning defective 3 0.000992 −1.28781 homolog (C. elegans) VPS37B vacuolar protein sorting 37 0.004355 −1.28765 homolog B (S. cerevisiae) CYP2B6 /// cytochrome P450, family 2, 0.001079 −1.2873 CYP2B7P1 subfamily B, polypeptide 6 /// cytochrome P450, family 2, su MALL mal, T-cell differentiation 0.000476 −1.28554 protein-like ALX4 ALX homeobox 4 1.18E−05 −1.28536 SOX15 SRY (sex determining region 0.000755 −1.28501 Y)-box 15 KRT5 keratin 5 0.000738 −1.28477 ESPL1 extra spindle pole bodies 0.003676 −1.28424 homolog 1 (S. cerevisiae) STARD8 StAR-related lipid transfer 0.00219 −1.28408 (START) domain containing 8 PSD3 pleckstrin and Sec7 domain 0.003653 −1.28307 containing 3 KIAA0195 KIAA0195 3.69E−05 −1.28154 MYO9B myosin IXB 0.000252 −1.27944 HIP1R /// huntingtin interacting protein 1 0.006353 −1.2794 LOC100294412 related /// similar to KIAA0655 protein EFNB1 ephrin-B1 0.000145 −1.27858 ERN1 endoplasmic reticulum to 0.001593 −1.27656 nucleus signaling 1 RHD Rh blood group, D antigen 0.005698 −1.27635 MFAP3L microfibrillar-associated protein 0.002875 −1.27538 3-like PLA1A phospholipase A1 member A 0.005885 −1.27427 POFUT2 protein O-fucosyltransferase 2 0.004736 −1.27411 C8orf39 chromosome 8 open reading 0.002547 −1.27348 frame 39 CRYBB2 crystallin, beta B2 0.000156 −1.27288 CYP4A11 cytochrome P450, family 4, 0.000381 −1.27285 subfamily A, polypeptide 11 PVRL2 poliovirus receptor-related 2 0.007308 −1.27216 (herpesvirus entry mediator B) CLCNKB chloride channel Kb 0.001537 −1.27136 MRAS muscle RAS oncogene homolog 0.002321 −1.27101 NFIB nuclear factor I/B 0.000362 −1.2706 FKSG2 apoptosis inhibitor 0.003687 −1.27027 SLC11A2 solute carrier family 11 (proton- 0.008176 −1.26987 coupled divalent metal ion transporters), member 2 FZR1 fizzy/cell division cycle 20 0.006166 −1.26883 related 1 (Drosophila) ZNF550 zinc finger protein 550 0.00302 −1.26876 GLP1R glucagon-like peptide 1 receptor 0.001684 −1.26854 SLC19A1 solute carrier family 19 (folate 0.003885 −1.26843 transporter), member 1 RTN2 reticulon 2 0.008304 −1.26775 PAPOLA poly(A) polymerase alpha 0.009359 −1.2676 STC1 stanniocalcin 1 0.001341 −1.26734 GK glycerol kinase 0.004541 −1.26678 EXOSC6 exosome component 6 0.00268 −1.26637 — — 4.96E−05 −1.26602 RAPSN receptor-associated protein of 0.003697 −1.26598 the synapse HFE hemochromatosis 0.000648 −1.26583 EHD2 EH-domain containing 2 0.001249 −1.26575 RIOK3 RIO kinase 3 (yeast) 0.004132 −1.26516 UBE2I Ubiquitin-conjugating enzyme 0.00062 −1.26466 E2I (UBC9 homolog, yeast) C15orf2 chromosome 15 open reading 0.002573 −1.26354 frame 2 DMD dystrophin 0.006011 −1.26327 PRLH prolactin releasing hormone 0.001657 −1.26177 MAP2K2 Mitogen-activated protein 0.001555 −1.26176 kinase kinase 2 TP63 tumor protein p63 0.001463 −1.26066 DACH1 dachshund homolog 1 0.002299 −1.26061 (Drosophila) PPP5C protein phosphatase 5, catalytic 0.002092 −1.26051 subunit SLC26A1 solute carrier family 26 (sulfate 0.000553 −1.26034 transporter), member 1 NUDT7 nudix (nucleoside diphosphate 0.004276 −1.25953 linked moiety X)-type motif 7 KCNJ12 potassium inwardly-rectifying 0.000307 −1.25907 channel, subfamily J, member 12 ENTPD7 ectonucleoside triphosphate 0.00881 −1.25885 diphosphohydrolase 7 SLC26A1 solute carrier family 26 (sulfate 0.000894 −1.25847 transporter), member 1 PRRG3 proline rich Gla (G- 0.001239 −1.25847 carboxyglutamic acid) 3 (transmembrane) RGS6 regulator of G-protein signaling 6 0.007795 −1.25638 ZBED2 zinc finger, BED-type 0.000482 −1.25597 containing 2 — — 1.57E−05 −1.25554 FICD FIC domain containing 0.005002 −1.25533 ARHGAP1 Rho GTPase activating protein 1 0.002967 −1.25434 ARHGDIA Rho GDP dissociation inhibitor 0.00427 −1.25429 (GDI) alpha SDHB succinate dehydrogenase 0.003554 −1.25315 complex, subunit B, iron sulfur Ip) AMHR2 anti-Mullerian hormone 0.000653 −1.25279 receptor, type II ABCA4 ATP-binding cassette, sub- 0.001332 −1.25263 family A (ABC1), member 4 TCF20 transcription factor 20 (AR1) 0.005851 −1.2525 BGN biglycan 0.00473 −1.25217 CASP7 caspase 7, apoptosis-related 0.003516 −1.25129 cysteine peptidase LPAR4 lysophosphatidic acid receptor 4 0.005372 −1.25127 GNA12 guanine nucleotide binding 0.009051 −1.2511 protein (G protein) alpha 12 CYP2W1 cytochrome P450, family 2, 0.00037 −1.25048 subfamily W, polypeptide 1 — — 0.005763 −1.25006 RAX retina and anterior neural fold 0.002983 −1.24963 homeobox C4A /// C4B /// complement component 4A 0.002229 −1.24845 LOC100292046 /// (Rodgers blood group) /// LOC100294156 complement component 4B (Chido blood ELAVL4 ELAV (embryonic lethal, 0.005864 −1.24796 abnormal vision, Drosophila)- like 4 (Hu antigen D) PXN paxillin 0.00025 −1.24781 ESR2 estrogen receptor 2 (ER beta) 0.000571 −1.24778 MYL10 myosin, light chain 10, 0.002715 −1.24748 regulatory EFS embryonal Fyn-associated 0.004955 −1.24747 substrate TFF3 trefoil factor 3 (intestinal) 0.000444 −1.24739 ADAM22 ADAM metallopeptidase 0.000495 −1.24728 domain 22 SRPK1 SFRS protein kinase 1 0.008451 −1.24704 LOC441601 septin 7 pseudogene 8.14E−05 −1.24632 BIRC5 baculoviral IAP repeat- 0.000591 −1.24548 containing 5 CCT8L2 chaperonin containing TCP1, 0.0033 −1.24521 subunit 8 (theta)-like 2 PPAP2B phosphatidic acid phosphatase 0.008026 −1.2452 type 2B CMA1 chymase 1, mast cell 0.000993 −1.245 APOA2 apolipoprotein A-II 0.000594 −1.24371 KDELR2 KDEL (Lys-Asp-Glu-Leu) 0.007788 −1.24358 endoplasmic reticulum protein retention receptor 2 ASCL3 achaete-scute complex homolog 0.00054 −1.24293 3 (Drosophila) RLINX1 runt-related transcription 0.0054 −1.24289 factor 1 BUB1 budding uninhibited by 0.000294 −1.24284 benzimidazoles 1 homolog (yeast) — — 0.003969 −1.24241 SLC6A8 solute carrier family 6 0.000656 −1.24067 (neurotransmitter transporter, creatine), member 8 HNRNPC /// heterogeneous nuclear 0.008367 −1.24043 HNRNPCL1 /// ribonucleoprotein C (C1/C2) /// LOC440563 /// heterogeneous nuclear LOC649330 ribonucleop RIBC2 RIB43A domain with coiled- 4.24E−05 −1.24036 coils 2 CLIC4 chloride intracellular channel 4 0.005848 −1.24019 RAB17 RAB17, member RAS 0.001346 −1.24001 oncogene family SCML2 sex comb on midleg-like 2 0.008595 −1.23921 (Drosophila) SPINLW1 serine peptidase inhibitor-like, 9.13E−05 −1.23909 with Kunitz and WAP domains 1 (eppin) ANK1 ankyrin 1, erythrocytic 0.006497 −1.23867 EDA2R ectodysplasin A2 receptor 0.004698 −1.2385 — — 0.003041 −1.23803 — — 0.000661 −1.23797 HTR4 5-hydroxytryptamine 1.84E−05 −1.2378 (serotonin) receptor 4 CDC42EP4 CDC42 effector protein (Rho 0.001214 −1.23768 GTPase binding) 4 KANK2 KN motif and ankyrin repeat 0.000895 −1.23765 domains 2 ANK1 ankyrin 1, erythrocytic 0.009625 −1.2373 ITGB3 integrin, beta 3 (platelet 0.001114 −1.23728 glycoprotein IIIa, antigen CD61) SYN1 synapsin I 0.005147 −1.23728 DUX3 /// double homeobox, 3 /// double 0.007355 −1.23705 DUX4 /// homeobox, 4 /// FSHD region FRG2C /// gene 2 family, member C /// s HPX-2 /// LOC100134409 /// LOC652119 /// LOC653543 /// LOC653544 /// LOC653545 /// LOC728410 PKNOX2 PBX/knotted 1 homeobox 2 0.005082 −1.23701 MLLT4 myeloid/lymphoid or mixed- 0.002526 −1.23601 lineage leukemia (trithorax homolog, Drosophila); translocate APOA2 apolipoprotein A-II 0.004185 −1.23591 PENK proenkephalin 0.000174 −1.23569 GNAT1 guanine nucleotide binding 0.00958 −1.23545 protein (G protein), alpha transducing activity polypeptide FURIN furin (paired basic amino acid 0.006444 −1.23543 cleaving enzyme) SEMA6A sema domain, transmembrane 0.000683 −1.23507 domain (TM), and cytoplasmic domain, (semaphorin) 6A EGFL6 EGF-like-domain, multiple 6 0.000502 −1.23478 HRH1 histamine receptor H1 0.008279 −1.23466 TSPAN1 tetraspanin 1 0.002802 −1.23452 DBC1 deleted in bladder cancer 1 0.001766 −1.23445 TRPC7 transient receptor potential 2.45E−07 −1.23402 cation channel, subfamily C, member 7 MDM2 Mdm2 p53 binding protein 0.008092 −1.23388 homolog (mouse) GPR52 G protein-coupled receptor 52 0.000198 −1.23387 HAMP hepcidin antimicrobial peptide 0.006054 −1.2333 PRSS2 protease, serine, 2 (trypsin 2) 0.001936 −1.2322 GPR107 G protein-coupled receptor 107 0.008739 −1.23212 FLJ11292 hypothetical protein FLJ11292 5.57E−05 −1.23211 FLJ20184 hypothetical protein FLJ20184 0.005162 −1.23203 B4GALT1 UDP-Gal: betaGlcNAc beta 1,4- 0.000192 −1.23117 galactosyltransferase, polypeptide 1 NKX3-1 NK3 homeobox 1 0.009204 −1.23108 ASIP agouti signaling protein, 0.002916 −1.23063 nonagouti homolog (mouse) SMAD4 SMAD family member 4 0.004268 −1.2306 EFCAB6 EF-hand calcium binding 0.000165 −1.23058 domain 6 GPR20 G protein-coupled receptor 20 0.008518 −1.23016 CA5A carbonic anhydrase VA, 0.004021 −1.22996 mitochondrial PLK4 polo-like 4 (Drosophila) 0.004056 −1.22981 TAAR5 trace amine associated 0.00273 −1.22947 receptor 5 SRPX2 sushi-repeat-containing 0.000298 −1.22939 protein, X-linked 2 CNTD2 cyclin N-terminal domain 1.28E−05 −1.22932 containing 2 AZGP1 alpha-2-glycoprotein 1, zinc- 0.004331 −1.22925 binding TIMP3 TIMP metallopeptidase 0.002046 −1.22923 inhibitor 3 RGS6 regulator of G-protein 0.006087 −1.22916 signaling 6 ADARB1 adenosine deaminase, RNA- 0.00212 −1.22908 specific, B1 (RED1 homolog rat) DYNC1I1 dynein, cytoplasmic 1, 0.000291 −1.22872 intermediate chain 1 C10orf10 chromosome 10 open reading 0.001942 −1.22872 frame 10 PDIA2 protein disulfide isomerase 0.001498 −1.22865 family A, member 2 PITX3 paired-like homeodomain 3 0.009246 −1.22861 HOXC13 homeobox C13 8.28E−05 −1.22836 LPAR3 lysophosphatidic acid receptor 3 0.001583 −1.22805 CTRC chymotrypsin C (caldecrin) 0.008361 −1.22773 CTSL2 cathepsin L2 0.005554 −1.2276 MUC8 mucin 8 0.005519 −1.22759 AQP5 aquaporin 5 0.000994 −1.22755 UGT1A1 /// UDP glucuronosyltransferase 1 0.001167 −1.22729 UGT1A10 /// family, polypeptide A1 /// UDP UGT1A4 /// glucuronosyltransferase 1 UGT1A6 /// UGT1A8 /// UGT1A9 KCNQ2 potassium voltage-gated 0.001293 −1.22727 channel, KQT-like subfamily, member 2 CYP2A13 cytochrome P450, family 2, 0.00551 −1.22653 subfamily A, polypeptide 13 ZNF155 zinc finger protein 155 0.005718 −1.22653 KIAA0892 KIAA0892 0.000223 −1.22645 ATP2A2 ATPase, Ca++ transporting, 0.008882 −1.22601 cardiac muscle, slow twitch 2 MMP26 matrix metallopeptidase 26 0.001265 −1.22581 FGF5 fibroblast growth factor 5 0.003695 −1.22569 FGF18 fibroblast growth factor 18 0.003001 −1.22556 FUT2 fucosyltransferase 2 (secretor 0.003882 −1.22538 status included) SHROOM2 shroom family member 2 0.000419 −1.22534 PRSS3 protease, serine, 3 0.006779 −1.22529 CREB3L1 cAMP responsive element 0.002111 −1.22516 binding protein 3-like 1 — — 0.008631 −1.22511 MGAT2 mannosyl (alpha-1,6-)- 0.006509 −1.2251 glycoprotein beta-1,2-N- acetylglucosaminyltransferase — — 0.000415 −1.2249 CSF1 colony stimulating factor 1 0.001088 −1.22487 (macrophage) SMAD3 SMAD family member 3 0.007701 −1.22479 PLCE1 Phospholipase C, epsilon 1 0.005157 −1.22464 MLXIPL MLX interacting protein-like 0.004864 −1.22443 OR10H3 olfactory receptor, family 10, 0.001893 −1.2243 subfamily H, member 3 — — 0.000353 −1.22418 ABCB11 ATP-binding cassette, sub- 0.004152 −1.224 family B (MDR/TAP), member 11 CD84 CD84 molecule 0.009088 −1.22398 ARHGEF4 Rho guanine nucleotide 0.005157 −1.22395 exchange factor (GEF) 4 ORC1L origin recognition complex, 0.003618 −1.22366 subunit 1-like (yeast) PCIF1 PDX1 C-terminal inhibiting 0.007109 −1.22348 factor 1 CD177 CD177 molecule 0.000868 −1.22342 — — 0.000414 −1.22314 C1orf116 chromosome 1 open reading 0.000626 −1.22307 frame 116 — — 0.000385 −1.2228 IFT122 intraflagellar transport 122 0.000359 −1.22277 homolog (Chlamydomonas) — — 0.000968 −1.22273 C11orf20 chromosome 11 open reading 0.002516 −1.2225 frame 20 DUSP13 dual specificity phosphatase 13 0.000847 −1.22179 C6orf208 chromosome 6 open reading 0.001257 −1.22163 frame 208 PLA2G5 phospholipase A2, group V 5.46E−05 −1.22142 PRAMEF1 /// PRAME family member 1 /// 0.001073 −1.22136 PRAMEF2 PRAME family member 2 CYP4F8 cytochrome P450, family 4, 0.001494 −1.22114 subfamily F, polypeptide 8 KCNA1 potassium voltage-gated 0.00046 −1.22105 channel, shaker-related subfamily, member 1 (episodic ataxia wi MFAP4 microfibrillar-associated 0.000166 −1.2209 protein 4 C6 complement component 6 0.006533 −1.22081 SLC4A3 solute carrier family 4, anion 0.009715 −1.22068 exchanger, member 3 IL1RAPL1 interleukin 1 receptor accessory 0.000271 −1.22049 protein-like 1 SERPINE1 serpin peptidase inhibitor, clade 0.001839 −1.22049 E (nexin, plasminogen activator inhibitor type 1), me ZCCHC14 zinc finger, CCHC domain 0.004618 −1.22042 containing 14 POLR3G polymerase (RNA) III (DNA 0.001007 −1.22028 directed) polypeptide G (32 kD) C16orf68 chromosome 16 open reading 0.006601 −1.22026 frame 68 FLJ14100 hypothetical protein FLJ14100 0.003745 −1.22017 SMCHD1 structural maintenance of 0.008572 −1.2201 chromosomes flexible hinge domain containing 1 ASCL1 achaete-scute complex homolog 0.002304 −1.21998 1 (Drosophila) FOXA2 forkhead box A2 0.00025 −1.2197 SLC23A2 solute carrier family 23 0.005914 −1.21969 (nucleobase transporters), member 2 KLK13 kallikrein-related peptidase 13 0.000211 −1.21966 MTSS1L metastasis suppressor 1-like 0.001589 −1.21956 DNMT3L DNA (cytosine-5-)- 0.000936 −1.21952 methyltransferase 3-like RREB1 ras responsive element binding 0.006278 −1.21948 protein 1 DNMBP dynamin binding protein 0.007794 −1.21943 PKLR pyruvate kinase, liver and RBC 0.000571 −1.21918 C1orf106 chromosome 1 open reading 0.005004 −1.21911 frame 106 CCDC134 coiled-coil domain containing 134 0.000478 −1.21888 MTSS1 metastasis suppressor 1 0.002441 −1.21878 CCDC40 coiled-coil domain containing 40 0.000701 −1.21869 HOXB1 homeobox B1 0.006406 −1.21825 SCNN1B sodium channel, nonvoltage- 0.001488 −1.2182 gated 1, beta SEMA4G sema domain, immunoglobulin 0.002662 −1.2182 domain (Ig), transmembrane domain (TM) and short cytoplasmi RAPGEFL1 Rap guanine nucleotide 0.000162 −1.21787 exchange factor (GEF)-like 1 MAGEL2 MAGE-like 2 0.000123 −1.21777 — — 0.000234 −1.21771 PLSCR2 phospholipid scramblase 2 0.000386 −1.21727 CHD2 chromodomain helicase DNA 0.000841 −1.21722 binding protein 2 PLCD1 phospholipase C, delta 1 0.005374 −1.2171 C1orf116 chromosome 1 open reading 0.006 −1.21704 frame 116 CHRNA2 cholinergic receptor, nicotinic, 0.008482 −1.21702 alpha 2 (neuronal) MBP myelin basic protein 0.008574 −1.21675 CDC42BPA CDC42 binding protein kinase 0.000334 −1.21665 alpha (DMPK-like) TNFRSF11A tumor necrosis factor receptor 0.007883 −1.21627 superfamily, member 11a, NFKB activator MYF6 myogenic factor 6 (herculin) 0.003356 −1.21615 PI15 peptidase inhibitor 15 0.004832 −1.21612 LOC440895 LIM and senescent cell antigen- 0.003588 −1.21578 like domains 3-like SBF1 SET binding factor 1 0.002572 −1.21568 MAST1 microtubule associated 0.001899 −1.21565 serine/threonine kinase 1 GLT8D2 glycosyltransferase 8 domain 0.000458 −1.21564 containing 2 ERBB3 v-erb-b2 erythroblastic 0.000806 −1.21564 leukemia viral oncogene homolog 3 (avian) LOH3CR2A loss of heterozygosity, 3, 0.004412 −1.21562 chromosomal region 2, gene A AMH anti-Mullerian hormone 0.000237 −1.21552 HR hairless homolog (mouse) 0.005332 −1.21547 RDH8 retinol dehydrogenase 8 (all- 0.000487 −1.21536 trans) PAWR PRKC, apoptosis, WT1, 0.005543 −1.2152 regulator DRD3 dopamine receptor D3 0.000203 −1.21493 CCT8 chaperonin containing TCP1, 0.009015 −1.21463 subunit 8 (theta) PRELP proline/arginine-rich end 0.007385 −1.21443 leucine-rich repeat protein SPOCK3 sparc/osteonectin, cwcv and 0.000394 −1.21434 kazal-like domains proteoglycan (testican) 3 EPS8L3 EPS8-like 3 0.007312 −1.21407 NXN nucleoredoxin 0.003294 −1.21404 SEMA4G sema domain, immunoglobulin 0.001706 −1.21395 domain (Ig), transmembrane domain (TM) and short cytoplasmi P2RY1 purinergic receptor P2Y, G- 0.002207 −1.21385 protein coupled, 1 AVL9 AVL9 homolog (S. cerevisiase) 0.002166 −1.21376 TEK TEK tyrosine kinase, 0.000493 −1.21369 endothelial MOGAT2 monoacylglycerol O- 0.002638 −1.21358 acyltransferase 2 KLK7 kallikrein-related peptidase 7 0.007089 −1.21357 MT1E /// metallothionein 1E /// 0.008728 −1.21355 MT1H /// metallothionein 1H /// MT1M metallothionein 1M CLDN18 claudin 18 0.002968 −1.21353 RHBDF2 rhomboid 5 homolog 2 0.007107 −1.21331 (Drosophila) SIX1 SIX homeobox 1 0.006149 −1.21304 INPP5A inositol polyphosphate-5- 0.00971 −1.21301 phosphatase, 40 kDa KCNMB3 potassium large conductance 0.007976 −1.213 calcium-activated channel, subfamily M beta member 3 MAP2K5 mitogen-activated protein 0.00099 −1.21293 kinase kinase 5 GPD1 glycerol-3-phosphate 0.003338 −1.21278 dehydrogenase 1 (soluble) LPO lactoperoxidase 0.001326 −1.21277 LOC729143 /// similar to Myosin phosphatase 0.007077 −1.21259 MPRIP Rho-interacting protein (Rho- interacting protein 3) (M-RI WNT7A wingless-type MMTV 0.004044 −1.21249 integration site family, member 7A — — 0.000279 −1.21223 RARG retinoic acid receptor, gamma 0.002589 −1.21222 CDH7 cadherin 7, type 2 0.004733 −1.2116 MBNL2 muscleblind-like 2 (Drosophila) 0.006252 −1.21154 RASGRP2 RAS guanyl releasing protein 2 0.007323 −1.21144 (calcium and DAG-regulated) RBMY2FP RNA binding motif protein, Y- 2.59E−05 −1.21141 linked, family 2, member F pseudogene MASP1 mannan-binding lectin serine 0.009232 −1.2109 peptidase 1 (C4/C2 activating component of Ra-reactive fac CASR calcium-sensing receptor 0.004273 −1.21088 EGR4 early growth response 4 0.001108 −1.21043 APOC2 apolipoprotein C-II 0.002122 −1.21042 HECW1 HECT, C2 and WW domain 0.005258 −1.2103 containing E3 ubiquitin protein ligase 1 HOXB3 homeobox B3 0.003953 −1.21029 IRF5 interferon regulatory factor 5 0.009858 −1.21029 NNMT nicotinamide N- 0.000406 −1.21028 methyltransferase AOC2 amine oxidase, copper 0.004428 −1.21023 containing 2 (retina-specific) ESRRG estrogen-related receptor 0.001335 −1.20993 gamma LPIN1 lipin 1 0.009736 −1.20987 ACOT11 acyl-CoA thioesterase 11 0.000945 −1.20973 CCDC33 coiled-coil domain containing 33 0.007172 −1.20945 MBD2 methyl-CpG binding domain 0.003023 −1.20941 protein 2 ZNF323 zinc finger protein 323 0.009551 −1.20931 NTRK2 neurotrophic tyrosine kinase, 0.000251 −1.20921 receptor, type 2 TMEM151B transmembrane protein 151B 0.009983 −1.20898 GPLD1 glycosylphosphatidylinositol 0.006394 −1.20848 specific phospholipase D1 LENEP lens epithelial protein 0.000284 −1.20832 HNF1B HNF1 homeobox B 0.001386 −1.20824 NXPH3 neurexophilin 3 0.001589 −1.20798 — — 0.006641 −1.20793 ALDH1A3 aldehyde dehydrogenase 1 0.000392 −1.20788 family, member A3 PHF20L1 PHD finger protein 20-like 1 0.002957 −1.20781 CKM creatine kinase, muscle 0.0008 −1.20774 — — 0.001361 −1.20746 PARD6B par-6 partitioning defective 6 0.000827 −1.20711 homolog beta (C. elegans) CRYGB crystallin, gamma B 0.005502 −1.20704 HAB1 B1 for mucin 0.001879 −1.20699 LARGE like-glycosyltransferase 0.009606 −1.20682 RAB40C RAB40C, member RAS 0.00324 −1.20676 oncogene family MPL myeloproliferative leukemia 0.007992 −1.20668 virus oncogene CHIT1 chitinase 1 (chitotriosidase) 0.003357 −1.20667 METTL10 methyltransferase like 10 0.003511 −1.20663 DUS4L dihydrouridine synthase 4-like 0.00298 −1.20661 (S. cerevisiae) PNLIPRP1 pancreatic lipase-related 0.000459 −1.20659 protein 1 ELL elongation factor RNA 0.001662 −1.20651 polymerase II ST8SIA5 ST8 alpha-N-acetyl- 0.000615 −1.20633 neuraminide alpha-2,8- sialyltransferase 5 ITGA8 integrin, alpha 8 0.009387 −1.20629 GRIN2B glutamate receptor, ionotropic, 0.000406 −1.20603 N-methyl D-aspartate 2B MC4R melanocortin 4 receptor 0.00036 −1.20584 RTDR1 rhabdoid tumor deletion region 0.000275 −1.20581 gene 1 HDAC6 histone deacetylase 6 0.001545 −1.2058 KCNJ13 potassium inwardly-rectifying 0.001433 −1.20567 channel, subfamily J, member 13 CPSF1 cleavage and polyadenylation 1.67E−05 −1.20546 specific factor 1, 160 kDa SPANXC SPANX family, member C 0.001064 −1.2054 CNOT4 CCR4-NOT transcription 0.007152 −1.20522 complex, subunit 4 LAMA2 Laminin, alpha 2 7.89E−05 −1.20506 SLC1A6 solute carrier family 1 (high 0.00372 −1.205 affinity aspartate/glutamate transporter), member 6 ABCA2 ATP-binding cassette, sub- 0.002267 −1.20494 family A (ABC1), member 2 KLK11 kallikrein-related peptidase 11 0.000758 −1.20493 GFRA3 GDNF family receptor alpha 3 0.002967 −1.2047 CYP3A4 cytochrome P450, family 3, 0.002771 −1.20468 subfamily A, polypeptide 4 SLC1A3 solute carrier family 1 (glial 0.004552 −1.20467 high affinity glutamate transporter), member 3 ATP2B2 ATPase, Ca++ transporting, 0.000594 −1.20453 plasma membrane 2 APBB2 amyloid beta (A4) precursor 0.005968 −1.20439 protein-binding, family B, member 2 VPS45 vacuolar protein sorting 45 0.000839 −1.20431 homolog (S. cerevisiae) GHRHR growth hormone releasing 0.003426 −1.20425 hormone receptor HOXD4 homeobox D4 0.004276 −1.20421 PRPH peripherin 4.94E−05 −1.20416 ADCY2 adenylate cyclase 2 (brain) 0.006778 −1.20412 LEFTY2 left-right determination factor 2 0.00084 −1.20391 CYP1B1 cytochrome P450, family 1, 0.002715 −1.20353 subfamily B, polypeptide 1 PCP4 Purkinje cell protein 4 2.27E−05 −1.20337 C8B complement component 8, beta 0.0017 −1.2033 polypeptide RANBP3 RAN binding protein 3 0.001832 −1.2033 PDE6H phosphodiesterase 6H, cGMP- 0.002496 −1.20303 specific, cone, gamma TRIM15 tripartite motif-containing 15 0.00027 −1.20261 VGLL1 vestigial like 1 (Drosophila) 0.001092 −1.20257 TRIM3 tripartite motif-containing 3 0.000537 −1.20249 LTBP4 latent transforming growth 0.000462 −1.20238 factor beta binding protein 4 CRKL v-crk sarcoma virus CT10 0.008611 −1.20236 oncogene homolog (avian)-like ADH7 alcohol dehydrogenase 7 (class 0.000166 −1.20227 IV), mu or sigma polypeptide PSG3 pregnancy specific beta-1- 0.00053 −1.20227 glycoprotein 3 GPR153 G protein-coupled receptor 153 0.008656 −1.20222 MFAP2 microfibrillar-associated 0.003428 −1.20216 protein 2 FGF13 fibroblast growth factor 13 0.002263 −1.20212 — — 0.007125 −1.202 NAPA N-ethylmaleimide-sensitive 0.006488 −1.20191 factor attachment protein, alpha ALDH3A1 aldehyde dehydrogenase 3 0.000897 −1.20175 family, member A1 MCM10 minichromosome maintenance 0.005216 −1.20168 complex component 10 TLE4 transducin-like enhancer of split 0.006143 −1.20166 4 (E(sp1) homolog, Drosophila) ITPR3 inositol 1,4,5-triphosphate 0.006944 −1.20157 receptor, type 3 CCDC87 coiled-coil domain containing 87 0.001771 −1.20124 C9orf7 chromosome 9 open reading 0.009273 −1.2011 frame 7 ACTC1 actin, alpha, cardiac muscle 1 0.00076 −1.20109 OBSL1 obscurin-like 1 0.002861 −1.20096 — — 0.000232 −1.20095 MAP2 microtubule-associated 0.003324 −1.20084 protein 2 CRYM crystallin, mu 0.005793 −1.20073 RNF122 ring finger protein 122 0.003704 −1.20071 SST somatostatin 0.003629 −1.2007 HLA-DRB6 major histocompatibility 0.009489 −1.20021 complex, class II, DR beta 6 (pseudogene) SLC22A17 solute carrier family 22, 0.00219 −1.20018 member 17 HSPG2 heparan sulfate proteoglycan 2 0.000654 −1.20017 HIP1 huntingtin interacting protein 1 4.28E−05 −1.20004 GRIK2 glutamate receptor, ionotropic, 3.13E−06 −1.19991 kainate 2 — — 0.008492 −1.19976 UNKL unkempt homolog 0.005034 −1.19954 (Drosophila)-like GPR144 G protein-coupled receptor 144 0.007186 −1.19948 KIR3DX1 killer cell immunoglobulin-like 0.003825 −1.1993 receptor, three domains, X1 — — 0.007994 −1.1993 NARFL nuclear prelamin A recognition 0.003052 −1.19926 factor-like — — 0.000127 −1.19903 UCP3 uncoupling protein 3 0.009564 −1.19903 (mitochondrial, proton carrier) — — 0.001429 −1.19877 PLXNA2 plexin A2 0.001989 −1.19862 BTN1A1 butyrophilin, subfamily 1, 0.003656 −1.19858 member A1 ERCC4 excision repair cross- 0.007138 −1.19837 complementing rodent repair deficiency, complementation group 4 CIITA class II, major 0.008237 −1.1982 histocompatibility complex, transactivator EGFR epidermal growth factor 0.008886 −1.19797 receptor (erythroblastic leukemia viral (v-erb-b) oncogene homo — — 0.005458 −1.19781 KRT33A keratin 33A 0.006693 −1.19769 CLTB Clathrin, light chain (Lcb) 0.008512 −1.19768 B3GALT5 UDP-Gal: betaGlcNAc beta 1,3- 0.001241 −1.19754 galactosyltransferase, polypeptide 5 — — 0.009616 −1.19751 AP3M2 adaptor-related protein complex 0.002731 −1.19749 3, mu 2 subunit GJC1 gap junction protein, gamma 1, 0.009693 −1.19749 45 kDa MYO3A myosin IIIA 0.000406 −1.19726 ADAM12 ADAM metallopeptidase 0.000608 −1.19713 domain 12 ARHGAP1 Rho GTPase activating protein 1 0.001148 −1.19713 PPP2R3A protein phosphatase 2 (formerly 0.002 −1.19703 2A), regulatory subunit B″, alpha CLIC4 chloride intracellular channel 4 0.00595 −1.19699 C20orf195 chromosome 20 open reading 0.005195 −1.19672 frame 195 SIGLEC8 sialic acid binding Ig-like 0.000256 −1.19653 lectin 8 GPRC5A G protein-coupled receptor, 0.002762 −1.19624 family C, group 5, member A CACNB1 calcium channel, voltage- 0.003107 −1.19613 dependent, beta 1 subunit MYL10 myosin, light chain 10, 0.009335 −1.19609 regulatory PRLR prolactin receptor 0.000985 −1.19602 OR2S2 olfactory receptor, family 2, 0.003564 −1.19593 subfamily S, member 2 NCR2 Natural cytotoxicity triggering 0.005113 −1.19575 receptor 2 CHAF1B chromatin assembly factor 1, 8.04E−05 −1.19574 subunit B (p60) EYA3 eyes absent homolog 3 0.005876 −1.19566 (Drosophila) CDS1 CDP-diacylglycerol synthase 0.006301 −1.19565 (phosphatidate cytidylyltransferase) 1 FBXL18 F-box and leucine-rich repeat 6.72E−06 −1.1956 protein 18 — — 3.49E−05 −1.19547 — — 0.006093 −1.19544 ADAM22 ADAM metallopeptidase 0.000119 −1.19543 domain 22 ACTL6B actin-like 6B 0.001385 −1.19543 ZNF821 zinc finger protein 821 0.002862 −1.19538 C16orf71 chromosome 16 open reading 0.006501 −1.19537 frame 71 HBBP1 hemoglobin, beta pseudogene 1 0.006504 −1.19525 PLXNA1 plexin A1 0.003653 −1.1951 CDC45L CDC45 cell division cycle 45- 0.00364 −1.19488 like (S. cerevisiae) MTCP1 mature T-cell proliferation 1 0.002145 −1.19479 PLCB4 phospholipase C, beta 4 0.006205 −1.19469 PLVAP plasmalemma vesicle associated 0.007844 −1.19456 protein PROX1 prospero homeobox 1 0.003286 −1.19447 CYP3A43 cytochrome P450, family 3, 0.004232 −1.19391 subfamily A, polypeptide 43 ICHG1 Immunoglobulin heavy constant 0.000798 −1.1939 gamma 1 (G1m marker) RECQL5 RecQ protein-like 5 0.00231 −1.19387 IDUA Iduronidase, alpha-L- 0.007734 −1.19383 DLGAP4 discs, large (Drosophila) 0.009247 −1.19341 homolog-associated protein 4 PLXNB1 plexin B1 0.007795 −1.19307 HSD17B14 hydroxysteroid (17-beta) 0.002049 −1.19271 dehydrogenase 14 FOXP3 forkhead box P3 0.007901 −1.19261 C19orf26 chromosome 19 open reading 0.00256 −1.19219 frame 26 EPB41L1 erythrocyte membrane protein 0.000528 −1.19208 band 4.1-like 1 RBBP9 retinoblastoma binding 0.003886 −1.19197 protein 9 GJB4 gap junction protein, beta 4, 0.005636 −1.19173 30.3 kDa UPK1B uroplakin 1B 0.001588 −1.19168 CYP19A1 cytochrome P450, family 19, 0.002082 −1.1916 subfamily A, polypeptide 1 LOC55908 hepatocellular carcinoma- 0.002937 −1.1916 associated gene TD26 CLDN18 claudin 18 0.003193 −1.1916 C2orf72 chromosome 2 open reading 0.002873 −1.19147 frame 72 NTRK3 neurotrophic tyrosine kinase, 3.09E−05 −1.19142 receptor, type 3 NRXN2 neurexin 2 0.000836 −1.1914 SPDEF SAM pointed domain 0.000244 −1.19138 containing ets transcription factor IGH@ /// immunoglobulin heavy locus /// 0.001803 −1.19135 IGHD /// immunoglobulin heavy constant IGHG1 /// delta /// immunoglobulin h IGHM /// LOC100289944 /// VSIG6 ACRV1 acrosomal vesicle protein 1 0.003333 −1.19132 PHLDB1 pleckstrin homology-like 0.001717 −1.1913 domain, family B, member 1 SORBS1 sorbin and SH3 domain 0.00522 −1.19127 containing 1 — — 6.67E−05 −1.19122 HAPLN2 hyaluronan and proteoglycan 0.001502 −1.19118 link protein 2 FABP3 fatty acid binding protein 3, 0.003523 −1.19097 muscle and heart (mammary- derived growth inhibitor) EFS embryonal Fyn-associated 0.001768 −1.19081 substrate ACVR1B activin A receptor, type IB 0.00457 −1.19081 CHST3 carbohydrate (chondroitin 6) 0.001252 −1.19075 sulfotransferase 3 UGT2A1 /// UDP glucuronosyltransferase 2 0.000599 −1.19065 UGT2A2 family, polypeptide A1 /// UDP glucuronosyltransferase 2 TAF1 TAF1 RNA polymerase II, 0.007846 −1.1905 TATA box binding protein (TBP)-associated factor, 250 kDa MT4 metallothionen 4 0.002292 −1.19047 MFAP3 microfibrillar-associated 0.008836 −1.19025 protein 3 ETV5 ets variant 5 0.002412 −1.19021 UBQLN3 ubiquilin 3 0.001961 −1.1902 TBX10 T-box 10 0.001032 −1.19013 — — 0.00191 −1.18979 GJB1 gap junction protein, beta 1, 0.008453 −1.18979 32 kDa ABO ABO blood group (transferase 0.007208 −1.18959 A, alpha 1-3-N- acetylgalactosaminyltransferase; transferas SPINK5 serine peptidase inhibitor, Kazal 0.001357 −1.18917 type 5 ATAD4 ATPase family, AAA domain 0.000327 −1.18914 containing 4 CDH11 cadherin 11, type 2, OB- 0.000198 −1.18913 cadherin (osteoblast) CARD14 caspase recruitment domain 0.002462 −1.18906 family, member 14 ALPP /// alkaline phosphatase, placental 0.001709 −1.18902 ALPPL2 (Regan isozyme) /// alkaline phosphatase, placental-lik CBL Cas-Br-M (murine) ecotropic 0.009088 −1.18899 retroviral transforming sequence LRP4 low density lipoprotein 0.005919 −1.18889 receptor-related protein 4 CDKL2 cyclin-dependent kinase-like 2 0.00225 −1.18883 (CDC2-related kinase) SSX3 synovial sarcoma, X breakpoint 3 0.002688 −1.18867 DSG2 desmoglein 2 0.006638 −1.18848 SLC45A2 solute carrier family 45, 0.001818 −1.18847 member 2 LAMA4 laminin, alpha 4 0.00392 −1.18846 WFDC8 WAP four-disulfide core 0.001163 −1.18843 domain 8 HTR7 5-hydroxytryptamine 0.001731 −1.18841 (serotonin) receptor 7 (adenylate cyclase-coupled) EFNB3 ephrin-B3 0.005729 −1.18838 TUBB2B tubulin, beta 2B 0.000497 −1.18837 OR7E19P olfactory receptor, family 7, 0.001943 −1.18834 subfamily E, member 19 pseudogene PMS2L4 postmeiotic segregation 0.006959 −1.1883 increased 2-like 4 pseudogene ASAP3 ArfGAP with SH3 domain, 0.000269 −1.18819 ankyrin repeat and PH domain 3 FRZB frizzled-related protein 0.001369 −1.1881 PDLIM4 PDZ and LIM domain 4 0.003582 −1.18805 PVT1 Pvt1 oncogene (non-protein 0.001967 −1.18803 coding) TFR2 transferrin receptor 2 0.00593 −1.18802 AHI1 Abelson helper integration 0.008274 −1.18798 site 1 — — 0.001985 −1.18788 TAF4 TAF4 RNA polymerase II, 0.000919 −1.18784 TATA box binding protein (TBP)-associated factor, 135 kDa ADAMTSL2 ADAMTS-like 2 0.008834 −1.18783 CLDN4 claudin 4 0.000164 −1.1878 KIR2DL1 /// killer cell immunoglobulin-like 0.000231 −1.1878 KIR2DL2 /// receptor, two domains, long KIR2DL3 /// cytoplasmic tail, 1 /// kil KIR2DL5A /// KIR2DL5B /// KIR2DS1 /// KIR2DS2 /// KIR2DS3 /// KIR2DS4 /// KIR2DS5 /// KIR3DL2 /// KIR3DL3 /// KIR3DP1 /// LOC727787 RAPGEF5 Rap guanine nucleotide 0.002052 −1.18774 exchange factor (GEF) 5 CRMP1 collapsin response mediator 0.008402 −1.18763 protein 1 LDB3 LIM domain binding 3 0.000824 −1.18759 — — 0.001275 −1.18749 F11 coagulation factor XI 0.004401 −1.18745 USP46 ubiquitin specific peptidase 46 0.009226 −1.18742 PTN pleiotrophin 0.00012 −1.18707 IBSP integrin-binding sialoprotein 0.000822 −1.18706 SLC9A3 solute carrier family 9 0.003578 −1.18695 (sodium/hydrogen exchanger), member 3 FLRT3 fibronectin leucine rich 0.002107 −1.18691 transmembrane protein 3 TRIM17 tripartite motif-containing 17 0.002821 −1.18688 FGF17 fibroblast growth factor 17 0.005417 −1.18682 CAMK1G calcium/calmodulin-dependent 0.003767 −1.18654 protein kinase IG GLYR1 glyoxylate reductase 1 homolog 0.001708 −1.18625 (Arabidopsis) CSH1 chorionic somatomammotropin 0.000163 −1.18612 hormone 1 (placental lactogen) NTF3 neurotrophin 3 0.002903 −1.18611 ABHD6 abhydrolase domain containing 6 0.000573 −1.18608 TRIM15 tripartite motif-containing 15 0.002896 −1.18596 OR52A1 olfactory receptor, family 52, 0.002896 −1.18579 subfamily A, member 1 FGFR2 fibroblast growth factor 0.000178 −1.18567 receptor 2 ORAI2 ORAI calcium release-activated 0.007127 −1.18563 calcium modulator 2 — — 0.002783 −1.18518 — — 0.002321 −1.18507 C17orf53 chromosome 17 open reading 0.001902 −1.18505 frame 53 GLP1R glucagon-like peptide 1 receptor 0.003491 −1.1849 SL1T1 slit homolog 1 (Drosophila) 0.002042 −1.18475 TP63 tumor protein p63 0.006308 −1.18464 DDR1 discoidin domain receptor 0.007775 −1.18462 tyrosine kinase 1 CFTR cystic fibrosis transmembrane 0.000534 −1.18451 conductance regulator (ATP- binding cassette sub-family C, DIO2 deiodinase, iodothyronine, 0.003653 −1.18445 type II LETM1 leucine zipper-EF-hand 0.005131 −1.18438 containing transmembrane protein 1 ACSM5 acyl-CoA synthetase medium- 0.000303 −1.18437 chain family member 5 — — 0.001738 −1.18434 ACTA1 actin, alpha 1, skeletal muscle 0.003411 −1.18432 NPR1 natriuretic peptide receptor 0.004745 −1.1842 A/guanylate cyclase A (atrionatriuretic peptide receptor A KCND3 potassium voltage-gated 0.008592 −1.18418 channel, ShaI-related subfamily, member 3 POPDC3 popeye domain containing 3 0.002195 −1.18411 DNAH3 dynein, axonemal, heavy chain 3 0.008169 −1.18403 SPDEF SAM pointed domain 0.007526 −1.18397 containing ets transcription factor CLEC4M C-type lectin domain family 4, 0.000696 −1.18389 member M — — 0.004001 −1.18375 SLC30A3 solute carrier family 30 (zinc 0.00669 −1.18367 transporter), member 3 NAGLU N-acetylglucosaminidase, 0.002574 −1.18361 alpha- AAK1 AP2 associated kinase 1 0.004007 −1.18358 DHX34 DEAH (Asp-Glu-Ala-His) box 0.002492 −1.18357 polypeptide 34 NNAT neuronatin 0.008336 −1.18355 — — 0.007629 −1.18337 AKAP9 A kinase (PRKA) anchor 0.00231 −1.18329 protein (yotiao) 9 ICMT isoprenylcysteine carboxyl 0.007841 −1.18329 methyltransferase FAM189A1 family with sequence similarity 0.007897 −1.18319 189, member A1 C10orf81 chromosome 10 open reading 0.009408 −1.18318 frame 81 MYOZ1 myozenin 1 0.008907 −1.18309 PKNOX2 PBX/knotted 1 homeobox 2 8.10E−05 −1.18298 MGC31957 hypothetical protein 0.001407 −1.18284 MGC31957 PRDM11 PR domain containing 11 0.004128 −1.18266 RET ret proto-oncogene 0.004396 −1.18265 IGHG1 Immunoglobulin heavy constant 0.002101 −1.18263 gamma 1 (G1m marker) XPNPEP2 X-prolyl aminopeptidase 0.004951 −1.18263 (aminopeptidase P) 2, membrane-bound NTRK2 neurotrophic tyrosine kinase, 7.26E-05 −1.18262 receptor, type 2 — — 0.009809 −1.1826 — — 0.004011 −1.18253 SLC25A10 solute carrier family 25 0.000841 −1.18243 (mitochondrial carrier; dicarboxylate transporter), member 10 NR1I2 nuclear receptor subfamily 1, 0.004273 −1.18219 group I, member 2 — — 0.0068 −1.18217 GRM8 glutamate receptor, 0.002678 −1.18202 metabotropic 8 OR3A3 olfactory receptor, family 3, 0.001803 −1.18201 subfamily A, member 3 GIPR gastric inhibitory polypeptide 0.001874 −1.1819 receptor PAH phenylalanine hydroxylase 0.001658 −1.18186 PACRG PARK2 co-regulated 0.007415 −1.18175 — — 0.003881 −1.18173 CLN8 ceroid-lipofuscinosis, neuronal 0.001987 −1.18166 8 (epilepsy, progressive with mental retardation) ZNF215 zinc finger protein 215 0.000173 −1.18165 TRIO Triple functional domain 0.003634 −1.1816 (PTPRF interacting) TTLL5 tubulin tyrosine ligase-like 0.008239 −1.18155 family, member 5 GRM1 glutamate receptor, 0.004897 −1.18148 metabotropic 1 PRKG1 protein kinase, cGMP- 0.002024 −1.18147 dependent, type I HHLA1 HERV-H LTR-associating 1 0.008614 −1.18137 LAMA3 laminin, alpha 3 0.002922 −1.18134 PTN pleiotrophin 0.002345 −1.18131 SLC37A4 solute carrier family 37 0.006933 −1.18114 (glucose-6-phosphate transporter), member 4 HOXC11 homeobox C11 0.000624 −1.18111 SLCO5A1 solute carrier organic anion 6.88E−05 −1.18102 transporter family, member 5A1 CA10 carbonic anhydrase X 0.001818 −1.18102 — — 0.005863 −1.18094 RRBP1 ribosome binding protein 1 0.000657 −1.1809 homolog 180 kDa (dog) SOD3 superoxide dismutase 3, 0.00355 −1.18082 extracellular NTRK3 neurotrophic tyrosine kinase, 0.003705 −1.18081 receptor, type 3 CYR61 cysteine-rich, angiogenic 0.003919 −1.18079 inducer, 61 STRA6 stimulated by retinoic acid gene 0.005735 −1.18068 6 homolog (mouse) SLC6A11 solute carrier family 6 0.007789 −1.18065 (neurotransmitter transporter, GABA), member 11 CNOT4 CCR4-NOT transcription 0.004365 −1.18064 complex, subunit 4 ATN1 Atrophin 1 0.004412 −1.18059 ITGB4 integrin, beta 4 0.001879 −1.18054 BCAP29 B-cell receptor-associated 0.005292 −1.18045 protein 29 — — 0.004726 −1.18036 NOVA2 neuro-oncological ventral 0.00162 −1.18035 antigen 2 — — 0.005358 −1.18035 RELN reelin 0.003425 −1.18034 LAMC2 laminin, gamma 2 0.006538 −1.18034 — — 0.003782 −1.18031 RAD51 RAD51 homolog (RecA 0.008493 −1.18024 homolog, E. coli) (S. cerevisiae) — — 0.000913 −1.18016 PRSS7 protease, serine, 7 0.005123 −1.18016 (enterokinase) DCBLD2 discoidin, CUB and LCCL 0.000493 −1.18007 domain containing 2 TACR2 tachykinin receptor 2 0.002078 −1.18003 RAB11B RAB11B, member RAS 0.004596 −1.17994 oncogene family OR2J2 olfactory receptor, family 2, 0.000236 −1.17993 subfamily J, member 2 VSNL1 visinin-like 1 0.001379 −1.17992 IFNA17 interferon, alpha 17 0.003586 −1.17985 DPYSL4 dihydropyrimidinase-like 4 0.00248 −1.17961 — — 0.009056 −1.17959 MGC2889 hypothetical protein MGC2889 0.001552 −1.17951 RRBP1 Ribosome binding protein 1 0.007965 −1.17935 homolog 180 kDa (dog) POLQ polymerase (DNA directed), 0.002209 −1.17934 theta OR1A2 olfactory receptor, family 1, 7.49E−06 −1.17927 subfamily A, member 2 PURA Purine-rich element binding 0.00771 −1.17918 protein A AIF1 allograft inflammatory factor 1 0.00406 −1.17917 CBS cystathionine-beta-synthase 0.008348 −1.17902 NECAB2 N-terminal EF-hand calcium 0.003146 −1.17901 binding protein 2 PRKCE protein kinase C, epsilon 0.003727 −1.17899 NOX1 NADPH oxidase 1 0.003303 −1.17898 IHH Indian hedgehog homolog 0.001392 −1.17891 (Drosophila) EXO1 exonuclease 1 0.002234 −1.17891 GPRIN2 G protein regulated inducer of 0.005827 −1.17888 neurite outgrowth 2 PDX1 pancreatic and duodenal 0.003138 −1.17881 homeobox 1 GPR12 G protein-coupled receptor 12 0.007938 −1.17835 — — 0.004616 −1.17827 FAM188A family with sequence similarity 0.005191 −1.17827 188, member A HS3ST3B1 heparan sulfate (glucosamine) 0.003282 −1.17824 3-O-sulfotransferase 3B1 ASCL1 achaete-scute complex homolog 0.000169 −1.17813 1 (Drosophila) ZNF484 zinc finger protein 484 0.000728 −1.1781 SERPINB3 serpin peptidase inhibitor, clade 5.85E−05 −1.17802 B (ovalbumin), member 3 CSH1 chorionic somatomammotropin 0.000315 −1.178 hormone 1 (placental lactogen) BCAN brevican 0.006433 −1.17796 DDN dendrin 0.005892 −1.17792 DUOX2 dual oxidase 2 0.002385 −1.17761 MORN1 MORN repeat containing 1 0.004195 −1.17751 SLC39A2 solute carrier family 39 (zinc 0.006145 −1.17751 transporter), member 2 CLCN7 chloride channel 7 0.00054 −1.17749 RUNX2 runt-related transcription factor 2 0.000734 −1.17741 TTYH1 tweety homolog 1 (Drosophila) 0.001039 −1.17723 ZNF280B zinc finger protein 280B 0.008339 −1.17716 PAX3 paired box 3 0.000716 −1.17714 LZTS1 leucine zipper, putative tumor 0.009862 −1.17712 suppressor 1 SLC8A2 solute carrier family 8 0.003583 −1.17706 (sodium/calcium exchanger), member 2 HAB1 B1 for mucin 0.00946 −1.17705 KIF1A kinesin family member 1A 0.002068 −1.17694 ARL4D ADP-ribosylation factor-like 4D 0.002302 −1.17694 UGT2B15 UDP glucuronosyltransferase 2 0.007983 −1.17694 family, polypeptide B15 NACA2 nascent polypeptide-associated 0.00631 −1.17693 complex alpha subunit 2 THRB thyroid hormone receptor, beta 0.000259 −1.17685 (erythroblastic leukemia viral (v-erb-a) oncogene homolo C6orf15 chromosome 6 open reading 0.004187 −1.17685 frame 15 — — 0.008907 −1.17685 GPR176 G protein-coupled receptor 176 0.00317 −1.17651 WSCD1 WSC domain containing 1 0.005206 −1.17645 PLXNB3 plexin B3 0.002725 −1.17642 CADM3 cell adhesion molecule 3 0.008183 −1.17636 HAP1 huntingtin-associated protein 1 2.19E−05 −1.17629 CYP1A2 cytochrome P450, family 1, 0.003159 −1.17629 subfamily A, polypeptide 2 SPAM1 sperm adhesion molecule 1 0.000727 −1.17625 (PH-20 hyaluronidase, zona pellucida binding) IL22RA1 interleukin 22 receptor, alpha 1 0.001309 −1.17617 CDC2L5 cell division cycle 2-like 5 0.007821 −1.17609 (cholinesterase-related cell division controller) IRX5 iroquois homeobox 5 0.000291 −1.17596 PPFIA2 protein tyrosine phosphatase, 0.001152 −1.17588 receptor type, f polypeptide (PTPRF), interacting protein — — 0.004585 −1.17587 KDELR3 KDEL (Lys-Asp-Glu-Leu) 0.000471 −1.17559 endoplasmic reticulum protein retention receptor 3 CEACAM7 carcinoembryonic antigen- 0.005552 −1.17556 related cell adhesion molecule 7 KCMF1 potassium channel modulatory 0.009164 −1.17553 factor 1 DUOX1 dual oxidase 1 0.008808 −1.17546 — — 0.000615 −1.17528 CDC27 cell division cycle 27 homolog 0.009706 −1.17522 (S. cerevisiae) HIST2H2AA3 histone cluster 2, H2aa3 0.002777 −1.17519 CAV3 caveolin 3 0.008482 −1.17519 APOA4 apolipoprotein A-IV 0.006002 −1.17518 — — 0.001198 −1.17511 NPR3 natriuretic peptide receptor 0.004663 −1.1751 C/guanylate cyclase C (atrionatriuretic peptide receptor C PRG3 proteoglycan 3 3.39E−05 −1.17507 TBC1D22B TBC1 domain family, member 22B 0.004838 −1.17506 TUSC3 tumor suppressor candidate 3 0.000348 −1.175 RIMS2 regulating synaptic membrane 0.005824 −1.175 exocytosis 2 CYP4F12 cytochrome P450, family 4, 0.007756 −1.1748 subfamily F, polypeptide 12 TBXA2R thromboxane A2 receptor 0.000835 −1.17478 HBEGF Heparin-binding EGF-like 0.001173 −1.17476 growth factor PSG9 pregnancy specific beta-1- 0.000597 −1.17461 glycoprotein 9 PYGO1 pygopus homolog 1 0.000119 −1.17423 (Drosophila) RASGRF1 Ras protein-specific guanine 0.007711 −1.17412 nucleotide-releasing factor 1 SCN2A sodium channel, voltage-gated, 0.005444 −1.17405 type II, alpha subunit KLHL1 kelch-like 1 (Drosophila) 0.003584 −1.17404 DTNB dystrobrevin, beta 0.005577 −1.17402 GREM1 gremlin 1, cysteine knot 0.008798 −1.17396 superfamily, homolog (Xenopus laevis) SNCG synuclein, gamma (breast 0.005937 −1.17388 cancer-specific protein 1) C22orf24 chromosome 22 open reading 0.000444 −1.17382 frame 24 PALM paralemmin 0.006745 −1.17378 COBLL1 COBL-like 1 0.003288 −1.17374 DNPEP aspartyl aminopeptidase 0.008863 −1.17361 MNS1 meiosis-specific nuclear 0.009321 −1.1735 structural 1 NFATC4 nuclear factor of activated T- 0.003566 −1.17336 cells, cytoplasmic, calcineurin- dependent 4 — — 0.001222 −1.1733 DLC1 deleted in liver cancer 1 0.009225 −1.17318 — — 0.002702 −1.17316 HSPC072 hypothetical LOC29075 0.003774 −1.17306 MCAM melanoma cell adhesion 0.00272 −1.17289 molecule CA12 carbonic anhydrase XII 0.006108 −1.17285 CSHL1 chorionic somatomammotropin 0.000243 −1.17282 hormone-like 1 RPAIN RPA interacting protein 0.000483 −1.17274 COL5A2 collagen, type V, alpha 2 0.004487 −1.1727 UGT1A8 /// UDP glucuronosyltransferase 1 3.79E−05 −1.17265 UGT1A9 family, polypeptide A8 /// UDP glucuronosyltransferase 1 IGH@ /// immunoglobulin heavy locus /// 0.002422 −1.17249 IGHA1 /// immunoglobulin heavy constant IGHG1 /// alpha 1 /// immunoglobulin IGHG2 /// IGHG3 /// IGHM /// LOC100126583 /// LOC100290036 /// LOC100290320 /// LOC100293211 /// LOC652494 ITGB1 integrin, beta 1 (fibronectin 0.001351 −1.17248 receptor, beta polypeptide, antigen CD29 includes MDF2, M TGFB2 transforming growth factor, 0.003578 −1.17248 beta 2 ACSM5 acyl-CoA synthetase medium- 0.00119 −1.17244 chain family member 5 — — 0.000204 −1.17236 ALOX12P2 arachidonate 12-lipoxygenase 0.00767 −1.17234 pseudogene 2 ERBB4 v-erb-a erythroblastic leukemia 0.006521 −1.17232 viral oncogene homolog 4 (avian) CLDN16 claudin 16 0.008608 −1.17225 CIB2 calcium and integrin binding 0.006423 −1.17213 family member 2 GALR3 galanin receptor 3 0.001999 −1.1721 MSMB microseminoprotein, beta- 0.000282 −1.17208 FABP7 fatty acid binding protein 7, 0.009982 −1.17199 brain ATXN3 ataxin 3 0.009922 −1.17197 KCNJ5 potassium inwardly-rectifying 0.00027 −1.17188 channel, subfamily J, member 5 TRDN triadin 0.005982 −1.1718 CYP3A43 cytochrome P450, family 3, 0.000729 −1.17176 subfamily A, polypeptide 43 BAZ2A bromodomain adjacent to zinc 0.000788 −1.17174 finger domain, 2A ACCN4 amiloride-sensitive cation 0.006157 −1.17166 channel 4, pituitary SILV silver homolog (mouse) 0.001891 −1.17163 DGCR14 DiGeorge syndrome critical 0.008083 −1.17146 region gene 14 SEMA6C sema domain, transmembrane 0.003714 −1.17139 domain (TM), and cytoplasmic domain, (semaphorin) 6C DIO2 deiodinase, iodothyronine, 0.001589 −1.17126 type II PTHLH parathyroid hormone-like 0.000476 −1.17108 hormone CSF3 colony stimulating factor 3 0.003909 −1.17105 (granulocyte) — — 0.002628 −1.17103 LEP leptin 0.006607 −1.17102 PDZRN3 PDZ domain containing ring 0.006658 −1.171 finger 3 RGSL1 regulator of G-protein signaling 0.000118 −1.17097 like 1 GJA4 gap junction protein, alpha 4, 0.002623 −1.17081 37 kDa F2 coagulation factor II (thrombin) 0.00539 −1.17065 SLC22A6 solute carrier family 22 (organic 0.002803 −1.17063 anion transporter), member 6 RASGRF1 Ras protein-specific guanine 0.000634 −1.17056 nucleotide-releasing factor 1 MAPRE2 microtubule-associated protein, 0.000948 −1.17055 RP/EB family, member 2 PVRL1 poliovirus receptor-related 1 0.008624 −1.17042 (herpesvirus entry mediator C) AKAP1 A kinase (PRKA) anchor 0.002224 −1.17036 protein 1 — — 0.001632 −1.17035 POMP proteasome maturation protein 0.00605 −1.17031 SOX21 SRY (sex determining region 0.003094 −1.17029 Y)-box 21 DNAH9 dynein, axonemal, heavy chain 9 0.001951 −1.1701 HOXC5 homeobox C5 0.005033 −1.17002 SERHL2 serine hydrolase-like 2 0.007046 −1.17001 KIAA0485 hypothetical LOC57235 0.005249 −1.16992 ITSN1 intersectin 1 (SH3 domain 0.004533 −1.16989 protein) B4GALT1 UDP-Gal: betaGlcNAc beta 1,4- 0.008844 −1.16988 galactosyltransferase, polypeptide 1 NEK2 NIMA (never in mitosis gene 0.002232 −1.16958 a)-related kinase 2 NUPR1 nuclear protein, transcriptional 0.007281 −1.16954 regulator, 1 CCDC93 coiled-coil domain containing 93 0.009039 −1.16948 EPO erythropoietin 0.00697 −1.16943 CRABP2 cellular retinoic acid binding 0.008297 −1.16942 protein 2 TYRO3 TYRO3 protein tyrosine kinase 0.002608 −1.16924 GOLGA2 golgi autoantigen, golgin 0.00754 −1.16892 subfamily a, 2 SEMA3F sema domain, immunoglobulin 0.008138 −1.1688 domain (Ig), short basic domain, secreted, (semaphorin) 3F BFSP2 beaded filament structural 0.009323 −1.16867 protein 2, phakinin NCAM1 neural cell adhesion molecule 1 0.001786 −1.16866 FOLH1 folate hydrolase (prostate- 0.002392 −1.16854 specific membrane antigen) 1 SSX2 synovial sarcoma, X breakpoint 2 0.001495 −1.16849 TMPRSS4 transmembrane protease, serine 4 0.002865 −1.16833 DCN decorin 0.007122 −1.16824 LPHN3 latrophilin 3 0.000384 −1.16821 POU4F3 POU class 4 homeobox 3 0.008224 −1.1682 CEACAM5 carcinoembryonic antigen- 0.007102 −1.16817 related cell adhesion molecule 5 BCL3 B-cell CLL/lymphoma 3 0.006056 −1.16816 — — 0.001654 −1.16813 EXTL3 exostoses (multiple)-like 3 0.007597 −1.16811 CCNA1 cyclin A1 0.00771 −1.16794 DDR2 discoidin domain receptor 0.002146 −1.16784 tyrosine kinase 2 PAX8 paired box 8 0.001053 −1.16778 SOX5 SRY (sex determining region 0.003283 −1.16769 Y)-box 5 POU3F1 POU class 3 homeobox 1 0.002775 −1.16762 PEX16 peroxisomal biogenesis factor 16 0.002334 −1.16754 IL4I1 /// interleukin 4 induced 1 /// 0.005035 −1.16752 NUP62 /// nucleoporin 62 kDa /// sialic SIGLEC11 acid binding Ig-like lectin 11 ALDOB aldolase B, fructose- 0.000319 −1.16747 bisphosphate GPC3 glypican 3 0.001612 −1.1674 IGFALS insulin-like growth factor 0.000261 −1.16732 binding protein, acid labile subunit WDR25 WD repeat domain 25 0.004535 −1.16731 FGF1 fibroblast growth factor 1 0.003604 −1.1673 (acidic) OSR2 odd-skipped related 2 0.005103 −1.1673 (Drosophila) ARID1A AT rich interactive domain 1A 0.007435 −1.16727 (SWI-like) GYPA glycophorin A (MNS blood 0.009414 −1.16715 group) KLK13 kallikrein-related peptidase 13 0.008814 −1.16712 PARVB parvin, beta 0.000462 −1.16709 LILRB5 leukocyte immunoglobulin-like 0.006486 −1.16709 receptor, subfamily B (with TM and ITIM domains), member RIMS2 regulating synaptic membrane 0.003506 −1.16705 exocytosis 2 C19orf21 chromosome 19 open reading 0.003213 −1.16704 frame 21 HOXD1 homeobox D1 0.00567 −1.16704 PRSS3 protease, serine, 3 0.007816 −1.167 FLT1 fms-related tyrosine kinase 1 0.002491 −1.16699 (vascular endothelial growth factor/vascular permeability ATP6V1C1 ATPase, H+ transporting, 0.00431 −1.16699 lysosomal 42 kDa, VI subunit C1 LOX lysyl oxidase 0.000711 −1.16681 CRYBB3 crystallin, beta B3 0.001902 −1.16676 CA12 carbonic anhydrase XII 0.006921 −1.16662 PRKG2 protein kinase, cGMP- 0.006891 −1.16659 dependent, type II MASP1 mannan-binding lectin serine 0.003795 −1.16655 peptidase 1 (C4/C2 activating component of Ra-reactive fac LOC728395 /// testis specific protein, Y-linked 9.49E−05 −1.16641 LOC728403 /// 1-like /// similar to Testis- TSPY1 specific Y-encoded prote PDCD1 programmed cell death 1 0.004701 −1.16634 GGTLC1 gamma-glutamyltransferase 0.004441 −1.16622 light chain 1 AQP8 aquaporin 8 0.004705 −1.16618 IL1F9 interleukin 1 family, member 9 0.00516 −1.16614 KRT16 keratin 16 0.0054 −1.16604 AICDA activation-induced cytidine 0.002152 −1.16602 deaminase BRD8 bromodomain containing 8 0.005311 −1.16593 C1orf95 Chromosome 1 open reading 0.003655 −1.16587 frame 95 OR3A2 olfactory receptor, family 3, 0.006942 −1.16583 subfamily A, member 2 — — 0.002314 −1.1656 PFKFB2 6-phosphofructo-2- 0.001095 −1.16553 kinase/fructose-2,6- biphosphatase 2 — — 0.007371 −1.16546 FRZB frizzled-related protein 0.004073 −1.16541 PAK3 p21 protein (Cdc42/Rac)- 0.001322 −1.16538 activated kinase 3 MEIS2 Meis homeobox 2 0.005478 −1.16537 ZSCAN2 zinc finger and SCAN domain 0.007216 −1.16537 containing 2 MYH7 myosin, heavy chain 7, cardiac 0.00763 −1.16506 muscle, beta VWA1 von Willebrand factor A 0.005843 −1.165 domain containing 1 LSAMP limbic system-associated 0.00683 −1.16484 membrane protein SRC v-src sarcoma (Schmidt-Ruppin 0.000259 −1.16471 A-2) viral oncogene homolog (avian) UGT1A1 /// UDP glucuronosyltransferase 1 0.002476 −1.16454 UGT1A10 /// family, polypeptide A1 /// UDP UGT1A3 /// glucuronosyltransferase 1 UGT1A4 /// UGT1A5 /// UGT1A6 /// UGT1A7 /// UGT1A8 /// UGT1A9 DIO1 deiodinase, iodothyronine, type I 0.002692 −1.16452 — — 0.009224 −1.16449 TADA3L transcriptional adaptor 3 0.00694 −1.16443 (NGG1 homolog, yeast)-like F10 coagulation factor X 0.004459 −1.16432 NFASC neurofascin homolog (chicken) 0.001454 −1.16431 CALCRL calcitonin receptor-like 0.001263 −1.16423 NBLA00301 Nbla00301 0.008572 −1.16423 MAB21L1 mab-21-like 1 (C. elegans) 0.006335 −1.16412 FBXO42 F-box protein 42 0.002917 −1.16408 COL10A1 collagen, type X, alpha 1 0.003871 −1.16407 CFB complement factor B 0.003696 −1.16404 SNX7 sorting nexin 7 0.007996 −1.16401 FOXN1 forkhead box N1 0.007972 −1.16365 SRY sex determining region Y 0.007481 −1.16363 HLF hepatic leukemia factor 0.009185 −1.16361 CLCA3P chloride channel accessory 3 0.00306 −1.16343 (pseudogene) DAZ1 /// deleted in azoospermia 1 /// 0.009345 −1.16343 DAZ2 /// deleted in azoospermia 2 /// DAZ3 /// deleted in azoospermia 3 /// DAZ4 GPR3 G protein-coupled receptor 3 0.001459 −1.16341 TMPRSS11E transmembrane protease, serine 11E 0.000617 −1.1634 EMID1 EMI domain containing 1 0.009937 −1.1634 KCNMB2 potassium large conductance 0.003215 −1.16335 calcium-activated channel, subfamily M, beta member 2 MUC5AC mucin 5AC, oligomeric 0.003908 −1.16324 mucus/gel-forming SORT1 sortilin 1 0.004071 −1.16318 HIF3A hypoxia inducible factor 3, 0.001905 −1.16316 alpha subunit — — 0.005107 −1.16312 MAPK4 mitogen-activated protein 0.005343 −1.16312 kinase 4 TCP11L1 t-complex 11 (mouse)-like 1 0.006965 −1.16308 ZZEF1 zinc finger, ZZ-type with EF- 0.009197 −1.16307 hand domain 1 DCAF7 DDB1 and CUL4 associated 0.00843 −1.16305 factor 7 DMWD dystrophia myotonica, WD 0.005744 −1.16304 repeat containing CLCA2 chloride channel accessory 2 0.000363 −1.16297 VAC14 Vac14 homolog (S. cerevisiae) 0.004469 −1.16297 CSPG5 chondroitin sulfate 8.48E−05 −1.16282 proteoglycan 5 (neuroglycan C) — — 0.005222 −1.16268 STMN2 stathmin-like 2 0.006817 −1.16268 MLLT4 myeloid/lymphoid or mixed- 0.003474 −1.16262 lineage leukemia (trithorax homolog, Drosophila); translocate GALNT14 UDP-N-acetyl-alpha-D- 0.008433 −1.16262 galactosamine: polypeptide N- acetylgalactosaminyltransferase 14 (Ga FGF12 fibroblast growth factor 12 0.000459 −1.16254 MFAP5 microfibrillar associated 0.008062 −1.16239 protein 5 SUMO3 SMT3 suppressor of mif two 3 0.006747 −1.16225 homolog 3 (S. cerevisiae) HTR3A 5-hydroxytryptamine 0.002037 −1.16224 (serotonin) receptor 3A GDF5 growth differentiation factor 5 0.006583 −1.16222 — — 0.008115 −1.16217 MMP24 matrix metallopeptidase 24 0.0086 −1.16211 (membrane-inserted) TSSK1B testis-specific serine kinase 1B 0.001104 −1.16208 CYP2A7P1 cytochrome P450, family 2, 0.002137 −1.16208 subfamily A, polypeptide 7 pseudogene 1 MARK1 MAP/microtubule affinity- 0.00508 −1.16207 regulating kinase 1 ATP1B2 ATPase, Na+/K+ transporting, 0.001769 −1.16204 beta 2 polypeptide TBX6 T-box 6 0.005223 −1.162 PAX8 paired box 8 0.001211 −1.16199 IL1R1 interleukin 1 receptor, type I 0.002307 −1.16176 RALYL RALY RNA binding protein- 0.004265 −1.16172 like OR2B2 olfactory receptor, family 2, 0.00135 −1.16157 subfamily B, member 2 TAAR3 trace amine associated receptor 0.00469 −1.16152 3 (gene/pseudogene) C12orf32 /// Chromosome 12 open reading 0.006624 −1.1615 IGHG1 /// frame 32 /// Immunoglobulin LOC642131 heavy constant gamma 1 (G1m mark DICER1 dicer 1, ribonuclease type III 0.003322 −1.16138 MMP28 matrix metallopeptidase 28 0.00533 −1.16138 GLRA3 glycine receptor, alpha 3 0.00029 −1.16137 PPARD peroxisome proliferator- 0.007231 −1.1612 activated receptor delta HSPA4L heat shock 70 kDa protein 4-like 0.001573 −1.16116 WNT2 wingless-type MMTV 0.009189 −1.16115 integration site family member 2 VIPR2 vasoactive intestinal peptide 0.005059 −1.16112 receptor 2 CYP2C9 Cytochrome P450, family 2, 0.001861 −1.16111 subfamily C, polypeptide 9 SRPX2 sushi-repeat-containing protein, 0.000138 −1.16109 X-linked 2 IGSF1 immunoglobulin superfamily, 0.001192 −1.16104 member 1 ALPK3 alpha-kinase 3 0.00608 −1.16101 TFPI tissue factor pathway inhibitor 0.006389 −1.16092 (lipoprotein-associated coagulation inhibitor) KCNS3 potassium voltage-gated 0.003038 −1.16085 channel, delayed-rectifier, subfamily S, member 3 MARCH8 membrane-associated ring 0.006576 −1.16083 finger (C3HC4) 8 FRMD4B FERM domain containing 4B 0.000444 −1.1607 TACR3 tachykinin receptor 3 0.00896 −1.16066 FIGF c-fos induced growth factor 0.005183 −1.16058 (vascular endothelial growth factor D) PDCD6 Programmed cell death 6 0.006092 −1.16044 TNN tenascin N 0.006607 −1.16044 SPANXB1 /// SPANX family, member B1 /// 0.001174 −1.16041 SPANXB2 /// SPANX family, member B2 /// SPANXF1 SPANX family, member F1 RHBDD3 rhomboid domain containing 3 0.000508 −1.16033 SPP2 secreted phosphoprotein 2, 0.005711 −1.16031 24 kDa PDE10A phosphodiesterase 10A 0.005387 −1.16026 ZNF224 zinc finger protein 224 0.009425 −1.16025 FGL1 fibrinogen-like 1 0.004849 −1.1602 PGAM2 phosphoglycerate mutase 2 0.003588 −1.16019 (muscle) CADM4 cell adhesion molecule 4 0.004403 −1.1601 APOBEC2 apolipoprotein B mRNA editing 0.007177 −1.15988 enzyme, catalytic polypeptide- like 2 SLC9A5 solute carrier family 9 0.003795 −1.15983 (sodium/hydrogen exchanger), member 5 SERPINA3 serpin peptidase inhibitor, clade 0.001263 −1.15982 A (alpha-1 antiproteinase, antitrypsin), member 3 GNAT1 guanine nucleotide binding 1.43E−05 −1.15969 protein (G protein), alpha transducing activity polypeptide — — 0.003568 −1.15968 ARHGEF16 Rho guanine exchange factor 0.004721 −1.15963 (GEF) 16 SMARCA2 SWI/SNF related, matrix 0.00734 −1.15962 associated, actin dependent regulator of chromatin, subfamily a DNAH9 dynein, axonemal, heavy chain 9 0.009008 −1.15957 RBM26 RNA binding motif protein 26 0.00116 −1.15955 WNT2B wingless-type MMTV 0.004131 −1.1595 integration site family, member 2B KCNK2 potassium channel, subfamily 0.00217 −1.15945 K, member 2 NPBWR2 neuropeptides B/W receptor 2 0.007611 −1.15945 SP2 Sp2 transcription factor 0.002898 −1.15944 — — 0.001126 −1.1594 TMPRSS11D transmembrane protease, 0.00681 −1.15937 serine 11D DENND2A DENN/MADD domain 0.003959 −1.15926 containing 2A TNIP3 TNFAIP3 interacting protein 3 0.006903 −1.15918 — — 0.009743 −1.15905 STC1 stanniocalcin 1 0.009242 −1.15902 DOCK6 dedicator of cytokinesis 6 0.007919 −1.15896 ADAM5P ADAM metallopeptidase 0.004414 −1.1589 domain 5 pseudogene SYDE1 synapse defective 1, Rho 0.002852 −1.15886 GTPase, homolog 1 (C. elegans) TNPO2 transportin 2 0.002767 −1.15883 LRTM1 leucine-rich repeats and 0.002691 −1.15877 transmembrane domains 1 USH1C Usher syndrome 1C (autosomal 0.006427 −1.15873 recessive, severe) PDE12 Phosphodiesterase 12 0.007267 −1.15873 SRCAP Snf2-related CREBBP activator 0.004676 −1.15866 protein OR10J1 olfactory receptor, family 10, 0.005572 −1.15866 subfamily J, member 1 OR2H2 olfactory receptor, family 2, 0.000927 −1.15859 subfamily H, member 2 KCNJ8 potassium inwardly-rectifying 0.008335 −1.15855 channel, subfamily J, member 8 — — 0.005451 −1.15854 RP11-257K9.7 hypothetical protein 0.002187 −1.15851 LOC100129128 DOCK5 dedicator of cytokinesis 5 0.000433 −1.1585 TPD52L1 tumor protein D52-like 1 0.005443 −1.15839 PAEP progestagen-associated 0.005702 −1.15836 endometrial protein — — 0.008347 −1.15836 GGA2 golgi associated, gamma 0.005179 −1.15822 adaptin ear containing, ARF binding protein 2 PHLDA3 pleckstrin homology-like 0.008165 −1.15821 domain, family A, member 3 HES2 hairy and enhancer of split 2 0.00726 −1.15816 (Drosophila) MLL myeloid/lymphoid or mixed- 0.00632 −1.15814 lineage leukemia (trithorax homolog, Drosophila) PTN pleiotrophin 0.001451 −1.15812 ITGB6 integrin, beta 6 0.000984 −1.1581 CHRNA6 cholinergic receptor, nicotinic, 0.008293 −1.15806 alpha 6 CIB2 calcium and integrin binding 0.004346 −1.15803 family member 2 — — 0.008761 −1.15788 PTPRF protein tyrosine phosphatase, 0.009748 −1.15777 receptor type, F TM7SF4 transmembrane 7 superfamily 0.007817 −1.15761 member 4 DAZ1 /// deleted in azoospermia 1 /// 0.001893 −1.15743 DAZ2 /// deleted in azoospermia 2 /// DAZ3 /// deleted in azoospermia 3 /// DAZ4 ALX1 ALX homeobox 1 0.000867 −1.15731 OR2F1 /// olfactory receptor, family 2, 0.009833 −1.15725 OR2F2 subfamily F, member 1 /// olfactory receptor, family 2, s — — 0.003275 −1.15723 PLAT plasminogen activator, tissue 0.005329 −1.15717 — — 0.00262 −1.15716 HGC6.3 similar to HGC6.3 0.00088 −1.15709 — — 0.002596 −1.15707 WNT11 wingless-type MMTV 0.003994 −1.15705 integration site family, member 11 PGK2 phosphoglycerate kinase 2 0.001775 −1.15699 SNAI2 snail homolog 2 (Drosophila) 0.001463 −1.15694 — — 0.001954 −1.15682 IL11 interleukin 11 0.005023 −1.15682 COL4A6 collagen, type IV, alpha 6 0.00986 −1.15677 PRUNE2 prune homolog 2 (Drosophila) 0.003014 −1.15675 — — 0.004631 −1.15658 ANKS1B ankyrin repeat and sterile alpha 0.000784 −1.15638 motif domain containing 1B — — 0.008146 −1.1563 LOC81691 exonuclease NEF-sp 0.008969 −1.15628 FERMT2 fermitin family homolog 2 0.006573 −1.15622 (Drosophila) TIMP3 TIMP metallopeptidase 0.005686 −1.15618 inhibitor 3 CST8 cystatin 8 (cystatin-related 0.006664 −1.15617 epididymal specific) CAPN6 calpain 6 0.006576 −1.15614 IDUA iduronidase, alpha-L- 0.002113 −1.15597 GPR32 G protein-coupled receptor 32 0.000773 −1.15585 AKR1B10 aldo-keto reductase family 1, 0.007442 −1.15571 member B10 (aldose reductase) GRHL2 grainyhead-like 2 (Drosophila) 5.24E−07 −1.15561 FBXO24 F-box protein 24 0.003095 −1.1555 HSF4 heat shock transcription factor 4 0.007043 −1.15548 IGHG1 Immunoglobulin heavy constant 0.00779 −1.15512 gamma 1 (G1m marker) HCN2 hyperpolarization activated 0.006206 −1.15509 cyclic nucleotide-gated potassium channel 2 LRP12 low density lipoprotein-related 0.007931 −1.15508 protein 12 ADAM 18 ADAM metallopeptidase 0.006422 −1.15501 domain 18 ITGA2 integrin, alpha 2 (CD49B, alpha 0.005786 −1.15485 2 subunit of VLA-2 receptor) ARHGEF15 Rho guanine nucleotide 0.003722 −1.15475 exchange factor (GEF) 15 UGT1A1 /// UDP glucuronosyltransferase 1 0.004274 −1.1547 UGT1A10 /// family, polypeptide A1 /// UDP UGT1A7 /// glucuronosyltransferase 1 UGT1A8 GUCA2A guanylate cyclase activator 2A 0.003837 −1.15459 (guanylin) MDK midkine (neurite growth- 0.003419 −1.15451 promoting factor 2) ITIH1 inter-alpha (globulin) 0.003175 −1.15449 inhibitor H1 EGFR epidermal growth factor 0.004643 −1.15435 receptor (erythroblastic leukemia viral (v-erb-b) oncogene homo UGT1A1 /// UDP glucuronosyltransferase 1 0.008973 −1.15435 UGT1A10 /// family, polypeptide A1 /// UDP UGT1A3 /// glucuronosyltransferase 1 UGT1A4 /// UGT1A5 /// UGT1A6 /// UGT1A7 /// UGT1A8 /// UGT1A9 MYOG myogenin (myogenic factor 4) 0.001644 −1.15431 TMSB15A thymosin beta 15a 0.001935 −1.15428 TLX1 T-cell leukemia homeobox 1 0.005999 −1.15425 EDNRA endothelin receptor type A 0.002498 −1.15397 LOC100289791 hypothetical protein 0.00917 −1.1539 LOC100289791 MDFI MyoD family inhibitor 0.008115 −1.15389 ZER1 zer-1 homolog (C. elegans) 0.003119 −1.15387 MYH15 myosin, heavy chain 15 0.00261 −1.15381 CDH20 cadherin 20, type 2 0.004804 −1.15374 GPR63 G protein-coupled receptor 63 0.003041 −1.15367 — — 0.009921 −1.15354 LOC440345 /// hypothetical protein 0.002618 −1.15347 LOC440354 /// LOC440345 /// PI-3-kinase- LOC595101 /// related kinase SMG-1 LOC641298 /// pseudogene /// PI-3 SMG1 HOXC10 homeobox C10 0.000495 −1.15345 KRTAP1-1 keratin associated protein 1-1 8.96E−06 −1.15325 ARSD arylsulfatase D 0.004513 −1.15315 CPLX3 /// complexin 3 /// lectin, mannose- 0.004705 −1.15295 LMAN1L binding, 1 like IFNA4 interferon, alpha 4 0.004607 −1.15289 ABCC1 ATP-binding cassette, sub- 0.006325 −1.15283 family C (CFTR/MRP), member 1 SEMA3E sema domain, immunoglobulin 0.004174 −1.15277 domain (Ig), short basic domain, secreted, (semaphorin) 3E MRE11A MRE11 meiotic recombination 0.003835 −1.15276 11 homolog A (S. cerevisiae) C1QL1 Complement component 1, q 0.004524 −1.15267 subcomponent-like 1 LIPF lipase, gastric 0.00095 −1.15265 TRIM9 tripartite motif-containing 9 0.008678 −1.15258 BBOX1 butyrobetaine (gamma), 2- 0.001994 −1.15252 oxoglutarate dioxygenase (gamma-butyrobetaine hydroxylase) 1 LRRC17 leucine rich repeat containing 17 0.005074 −1.15235 WNT2B wingless-type MMTV 0.006181 −1.15231 integration site family, member 2B CYP3A4 cytochrome P450, family 3, 0.007633 −1.15227 subfamily A, polypeptide 4 SI sucrase-isomaltase (alpha- 0.001001 −1.1522 glucosidase) ANO3 anoctamin 3 0.00341 −1.15219 OBSL1 obscurin-like 1 0.003099 −1.15215 — — 0.007073 −1.152 CHRD chordin 0.004608 −1.15192 MSX2 msh homeobox 2 0.009125 −1.15179 PSG1 pregnancy specific beta-1- 0.00029 −1.15178 glycoprotein 1 FAM107A family with sequence similarity 0.001347 −1.15167 107, member A LRRC37B2 leucine rich repeat containing 0.001053 −1.15156 37, member B2 ANKLE2 Ankyrin repeat and LEM 0.004674 −1.15155 domain containing 2 PAX2 paired box 2 0.004533 −1.15149 UNC5B Unc-5 homolog B (C. elegans) 0.001994 −1.15124 ADCYAP1R1 adenylate cyclase activating 0.001818 −1.15119 polypeptide 1 (pituitary) receptor type I HFE hemochromatosis 0.0019 −1.15119 — — 0.006488 −1.15106 SYT1 synaptotagmin 1 0.002216 −1.15088 GJC2 gap junction protein, gamma 2, 0.006151 −1.15082 47 kDa LOC100293871 similar to PRO2325 0.005525 −1.15064 FGF8 fibroblast growth factor 8 0.008777 −1.15061 (androgen-induced) ACRV1 acrosomal vesicle protein 1 0.005022 −1.15056 NRXN1 neurexin 1 0.004617 −1.15047 GDPD2 glycerophosphodiester 0.004533 −1.15039 phosphodiesterase domain containing 2 RGS4 regulator of G-protein 0.003963 −1.15033 signaling 4 CELA2A chymotrypsin-like elastase 7.18E−05 −1.15022 family, member 2A IFNW1 interferon, omega 1 0.001727 −1.15017 MLNR motilin receptor 0.000122 −1.15014 RNF17 ring finger protein 17 0.003651 −1.15006 LAD1 ladinin 1 0.001937 −1.15 GLRA2 glycine receptor, alpha 2 0.006763 −1.14955 RASL12 RAS-like, family 12 0.000306 −1.14945 MAGOH2 mago-nashi homolog 2, 0.003414 −1.14942 proliferation-associated (Drosophila) C6orf54 chromosome 6 open reading 0.007125 −1.14931 frame 54 — — 0.001197 −1.14922 ZNF214 zinc finger protein 214 0.000481 −1.1492 IKBKG inhibitor of kappa light 0.005732 −1.14913 polypeptide gene enhancer in B-cells, kinase gamma AP4E1 adaptor-related protein complex 0.004158 −1.14904 4, epsilon 1 subunit ZNRF4 zinc and ring finger 4 0.000445 −1.14875 OSBPL10 oxysterol binding protein-like 10 0.008717 −1.14862 C1orf175 /// chromosome 1 open reading 0.002146 −1.14841 TTC4 frame 175 /// tetratricopeptide repeat domain 4 PCDHB3 protocadherin beta 3 0.006249 −1.14837 ADRBK1 adrenergic, beta, receptor 0.009822 −1.14828 kinase 1 ITSN1 intersectin 1 (SH3 domain 0.002166 −1.14826 protein) XAGE1A /// X antigen family, member 1A /// 0.00656 −1.1482 XAGE1B /// X antigen family, member XAGE1C /// 1B /// X antigen family, membe XAGE1D /// XAGE1E CDH22 cadherin-like 22 0.008849 −1.14819 FARP2 FERM, RhoGEF and pleckstrin 0.002273 −1.14813 domain protein 2 MYT1 myelin transcription factor 1 0.003875 −1.14809 TNC Tenascin C 0.004194 −1.14799 MUC5AC mucin 5AC, oligomeric 0.009053 −1.14791 mucus/gel-forming SLC6A15 solute carrier family 6 (neutral 0.008601 −1.1479 amino acid transporter), member 15 PP14571 similar to hCG1777210 0.004733 −1.14789 SMR3A /// submaxillary gland androgen 0.002495 −1.14788 SMR3B regulated protein 3A /// submaxillary gland androgen regula RXRG retinoid X receptor, gamma 0.006609 −1.14772 SNX1 sorting nexin 1 0.004678 −1.14771 GLP1R glucagon-like peptide 1 receptor 0.00094 −1.14751 C6orf155 chromosome 6 open reading 0.000855 −1.14743 frame 155 ATP1A2 ATPase, Na+/K+ transporting, 0.005511 −1.14737 alpha 2 (+) polypeptide TFAP4 transcription factor AP-4 0.006392 −1.14734 (activating enhancer binding protein 4) PNPLA2 Patatin-like phospholipase 0.005616 −1.14727 domain containing 2 DIRAS3 DIRAS family, GTP-binding 0.008453 −1.14717 RAS-like 3 ANO2 anoctamin 2 0.000478 −1.14709 TACSTD2 tumor-associated calcium signal 0.003737 −1.14682 transducer 2 MCM3AP minichromosome maintenance 0.000118 −1.14681 complex component 3 associated protein IL13RA2 interleukin 13 receptor, alpha 2 0.002253 −1.14678 TRIM10 tripartite motif-containing 10 0.005191 −1.14676 RTEL1 regulator of telomere elongation 0.008986 −1.14672 helicase 1 PRRX2 paired related homeobox 2 0.006073 −1.14659 TSHB thyroid stimulating hormone, 0.009948 −1.14656 beta TIMELESS timeless homolog (Drosophila) 0.005683 −1.14649 FMO1 flavin containing 0.006505 −1.14614 monooxygenase 1 KIF18A kinesin family member 18A 0.009581 −1.14614 KIAA1199 KIAA1199 0.002884 −1.14612 CALB2 calbindin 2 0.005686 −1.14598 MFAP3L microfibrillar-associated protein 0.00354 −1.14575 3-like PTGER3 prostaglandin E receptor 3 0.006984 −1.14569 (subtype EP3) EPAS1 endothelial PAS domain protein 1 0.005676 −1.14564 — — 0.000263 −1.14559 SQSTM1 sequestosome 1 0.009341 −1.14558 TSPY1 testis specific protein, Y-linked 1 0.002158 −1.14553 CPM Carboxypeptidase M 0.001695 −1.14545 DLGAP1 discs, large (Drosophila) 0.000345 −1.14542 homolog-associated protein 1 CYP4F11 cytochrome P450, family 4, 0.0029 −1.14536 subfamily F, polypeptide 11 TLX3 T-cell leukemia homeobox 3 0.003278 −1.14527 PCDHA10 protocadherin alpha 10 0.006222 −1.14513 TAOK2 TAO kinase 2 0.001305 −1.14511 ERC1 ELKS/RAB6-interacting/CAST 0.002053 −1.14511 family member 1 TBX2 T-box 2 0.005151 −1.14502 KALRN kalirin, RhoGEF kinase 0.008586 −1.14478 DICER1 dicer 1, ribonuclease type III 0.000825 −1.14473 PAPPA pregnancy-associated plasma 0.004805 −1.14473 protein A, pappalysin 1 — — 0.003479 −1.14468 — — 0.008082 −1.14467 KIF5A kinesin family member 5A 0.003962 −1.14458 DNAJC22 DnaJ (Hsp40) homolog, 0.007069 −1.14453 subfamily C, member 22 — — 0.006388 −1.14452 OTUB1 OTU domain, ubiquitin 0.007521 −1.14451 aldehyde binding 1 ITGBL1 integrin, beta-like 1 (with EGF- 0.005427 −1.14445 like repeat domains) KIAA1644 KIAA1644 0.009294 −1.14444 SEZ6L2 seizure related 6 homolog 0.005712 −1.14434 (mouse)-like 2 PCNXL2 pecanex-like 2 (Drosophila) 0.008015 −1.14434 HMHB1 histocompatibility (minor) HB-1 0.003775 −1.14427 ERG v-ets erythroblastosis virus E26 0.008735 −1.14427 oncogene homolog (avian) SNTB2 syntrophin, beta 2 (dystrophin- 0.004153 −1.14426 associated protein A1, 59 kDa, basic component 2) GJA5 gap junction protein, alpha 5, 0.003562 −1.14404 40 kDa AGTR2 angiotensin II receptor, type 2 0.007867 −1.14384 GJA3 gap junction protein, alpha 3, 0.000595 −1.14377 46 kDa GCK glucokinase (hexokinase 4) 0.005137 −1.14365 LRRC61 leucine rich repeat containing 61 0.008969 −1.14358 CNTF /// ciliary neurotrophic factor /// 0.000997 −1.14357 ZFP91 /// zinc finger protein 91 homolog ZFP91-CNTF (mouse) /// ZFP91-CNTF r PDLIM4 PDZ and LIM domain 4 0.008589 −1.14351 MPPED2 metallophosphoesterase domain 1.95E−05 −1.1435 containing 2 IFNA10 interferon, alpha 10 0.003286 −1.14346 ACTN2 actinin, alpha 2 0.005077 −1.14343 VGLL1 vestigial like 1 (Drosophila) 0.00531 −1.14337 GJA9 gap junction protein, alpha 9, 0.003777 −1.14331 59 kDa LDLR low density lipoprotein receptor 0.003143 −1.1433 ANK2 ankyrin 2, neuronal 0.001761 −1.14329 COL1A1 collagen, type I, alpha 1 0.004543 −1.14329 TIMP3 TIMP metallopeptidase 0.00282 −1.14323 inhibitor 3 OTOF otoferlin 0.006622 −1.14322 AGXT alanine-glyoxylate 0.005384 −1.14318 aminotransferase GLI2 GLI family zinc finger 2 0.008292 −1.14291 TRMT61A tRNA methyltransferase 61 0.00203 −1.1428 homolog A (S. cerevisiae) FOXD2 forkhead box D2 0.003543 −1.14275 TMEM212 transmembrane protein 212 0.003253 −1.14258 DENND2A DENN/MADD domain 0.007115 −1.14257 containing 2A B3GALT1 UDP-Gal: betaGlcNAc beta 1,3- 0.003568 −1.14256 galactosyltransferase, polypeptide 1 SPAG11A sperm associated antigen 11A 0.006235 −1.14249 MMP16 matrix metallopeptidase 16 0.008228 −1.1424 (membrane-inserted) PRDM4 PR domain containing 4 0.0049 −1.14239 TF transferrin 0.004293 −1.14233 ELF5 E74-like factor 5 (ets domain 0.004394 −1.14201 transcription factor) GSC2 goosecoid homeobox 2 0.000273 −1.14181 EPB41L4B erythrocyte membrane protein 0.003468 −1.14166 band 4.1 like 4B GYG2 glycogenin 2 0.009413 −1.14164 LYZL6 lysozyme-like 6 0.006035 −1.14149 DCHS2 dachsous 2 (Drosophila) 0.006341 −1.14146 OBP2A /// odorant binding protein 2A /// 0.00776 −1.14144 OBP2B odorant binding protein 2B ANGPTL3 angiopoietin-like 3 0.007619 −1.1414 MYH11 myosin, heavy chain 11, smooth 0.002648 −1.14138 muscle — — 0.00271 −1.1412 NES nestin 0.002731 −1.14119 SLC17A1 solute carrier family 17 (sodium 0.004803 −1.14111 phosphate), member 1 RBM15B RNA binding motif protein 15B 0.004537 −1.14109 CSH1 chorionic somatomammotropin 0.009332 −1.14094 hormone 1 (placental lactogen) HTR5A 5-hydroxytryptamine 0.000162 −1.1409 (serotonin) receptor 5A CYP3A7 cytochrome P450, family 3, 0.00199 −1.1409 subfamily A, polypeptide 7 HTR2A 5-hydroxytryptamine 0.004894 −1.14084 (serotonin) receptor 2A KCNV2 potassium channel, subfamily 0.005931 −1.14082 V, member 2 TOX3 TOX high mobility group box 0.001764 −1.14064 family member 3 CLOCK clock homolog (mouse) 0.006632 −1.14057 — — 0.006807 −1.14053 MAGEA6 melanoma antigen family A, 6 0.00046 −1.14048 — — 0.000518 −1.1404 FAM12A family with sequence similarity 0.001548 −1.14036 12, member A COL4A3 collagen, type IV, alpha 3 0.007446 −1.14035 (Goodpasture antigen) S1PR2 sphingosine-1-phosphate 0.008163 −1.14034 receptor 2 NAT8 N-acetyltransferase 8 (GCN5- 0.002654 −1.14031 related, putative) ACE2 angiotensin 1 converting 0.007666 −1.14031 enzyme (peptidyl-dipeptidase A) 2 SLC22A6 solute carrier family 22 (organic 0.00816 −1.14031 anion transporter), member 6 SLC13A2 solute carrier family 13 0.005043 −1.14029 (sodium-dependent dicarboxylate transporter), member 2 MYH4 myosin, heavy chain 4, skeletal 0.009604 −1.14029 muscle APBB2 amyloid beta (A4) precursor 0.009135 −1.14026 protein-binding, family B, member 2 RAP1GAP RAP1 GTPase activating 0.007618 −1.14025 protein SHOX2 short stature homeobox 2 0.004273 −1.14022 SLCO1A2 solute carrier organic anion 0.003589 −1.14006 transporter family, member 1A2 ETV1 ets variant 1 0.00888 −1.14001 MAGEA12 melanoma antigen family A, 12 0.003805 −1.13997 PLA2G6 phospholipase A2, group VI 0.006425 −1.13996 (cytosolic, calcium- independent) ADRA1A adrenergic, alpha-1A-, receptor 0.007465 −1.13995 — — 0.008637 −1.13992 SYT5 synaptotagmin V 0.004699 −1.1399 GPR161 G protein-coupled receptor 161 0.004773 −1.13989 SEMA3F sema domain, immunoglobulin 0.006736 −1.13975 domain (Ig), short basic domain, secreted, (semaphorin) 3F CYP3A43 cytochrome P450, family 3, 0.003382 −1.13964 subfamily A, polypeptide 43 HOMER2 homer homolog 2 (Drosophila) 0.003535 −1.13961 KCNJ5 potassium inwardly-rectifying 0.005942 −1.13913 channel, subfamily J, member 5 PPL periplakin 0.00221 −1.13899 COL17A1 collagen, type XVII, alpha 1 0.003115 −1.13894 CSHL1 chorionic somatomammotropin 0.004285 −1.13887 hormone-like 1 C9orf116 chromosome 9 open reading 0.004915 −1.13886 frame 116 PARK2 Parkinson disease (autosomal 0.00541 −1.13885 recessive, juvenile) 2, parkin UGT2B15 UDP glucuronosyltransferase 2 0.002586 −1.13876 family, polypeptide B15 — — 0.002677 −1.13855 CDK6 cyclin-dependent kinase 6 0.005041 −1.13851 FAM174B family with sequence similarity 0.00769 −1.13845 174, member B — — 6.02E−05 −1.13837 CELA2A /// chymotrypsin-like elastase 0.008746 −1.13825 CELA2B family, member 2A /// chymotrypsin-like elastase family, mem SPDEF SAM pointed domain 0.006039 −1.13824 containing ets transcription factor EPB41 erythrocyte membrane protein 0.00381 −1.13816 band 4.1 (elliptocytosis 1, RH- linked) GAB1 GRB2-associated binding 0.008578 −1.13811 protein 1 SMAD6 SMAD family member 6 0.002361 −1.13807 SMR3A submaxillary gland androgen 0.004041 −1.13806 regulated protein 3 A PDE6G phosphodiesterase 6G, cGMP- 0.009564 −1.13803 specific, rod, gamma COL5A1 collagen, type V, alpha 1 0.003287 −1.13787 ABCA6 ATP-binding cassette, sub- 0.008623 −1.13787 family A (ABC1), member 6 DMD dystrophin 0.000248 −1.13783 CYLC2 cylicin, basic protein of sperm 0.008464 −1.13771 head cytoskeleton 2 CIDEA cell death-inducing DFFA-like 0.007254 −1.13768 effector a RAG2 recombination activating gene 2 0.002984 −1.13757 HIST1H2BN histone cluster 1, H2bn 0.007319 −1.13751 FMO6P flavin containing 0.007564 −1.13747 monooxygenase 6 pseudogene — — 0.009453 −1.13738 MAOA monoamine oxidase A 0.004806 −1.13729 ANKRD53 ankyrin repeat domain 53 0.00488 −1.13725 HAPLN1 hyaluronan and proteoglycan 0.00865 −1.13719 link protein 1 MT1M metallothionein 1M 0.009364 −1.13718 EHD2 EH-domain containing 2 0.006795 −1.13713 GAD2 glutamate decarboxylase 2 0.007785 −1.13709 (pancreatic islets and brain, 65 kDa) CRISP2 cysteine-rich secretory protein 2 0.009143 −1.13708 CSN2 casein beta 0.006005 −1.13695 — — 0.006648 −1.13691 SULT1C2 sulfotransferase family, 0.001313 −1.13685 cytosolic, 1C, member 2 PCDHGA3 protocadherin gamma 0.002114 −1.13681 subfamily A, 3 SSX3 synovial sarcoma, X breakpoint 3 0.001106 −1.13668 FGFR2 fibroblast growth factor 0.006105 −1.13666 receptor 2 GPR161 G protein-coupled receptor 161 0.00957 −1.13664 ATN1 atrophin 1 0.009835 −1.13654 CHD5 chromodomain helicase DNA 0.007274 −1.13651 binding protein 5 A4GALT alpha 1,4-galactosyltransferase 0.001062 −1.13647 MYBPH myosin binding protein H 0.007527 −1.13634 CSHL1 chorionic somatomammotropin 0.002335 −1.1363 hormone-like 1 — — 0.004169 −1.13618 NCAPH2 non-SMC condensin II 0.0079 −1.13612 complex, subunit H2 CAPN9 calpain 9 0.003071 −1.13597 CNGB1 cyclic nucleotide gated channel 0.007125 −1.13588 beta 1 BCAM basal cell adhesion molecule 0.00753 −1.13578 (Lutheran blood group) DRD5 dopamine receptor D5 0.00281 −1.13557 NR5A2 nuclear receptor subfamily 5, 0.000913 −1.13547 group A, member 2 TEF thyrotrophic embryonic factor 0.004588 −1.13544 ELAVL2 ELAV (embryonic lethal, 0.002205 −1.13541 abnormal vision, Drosophila)- like 2 (Hu antigen B) DGKB diacylglycerol kinase, beta 0.00918 −1.13537 90 kDa HTR7P 5-hydroxytryptamine 0.00209 −1.13524 (serotonin) receptor 7 pseudogene RHAG Rh-associated glycoprotein 0.005396 −1.1352 GH2 growth hormone 2 0.006321 −1.13519 — — 0.000833 −1.13517 — — 0.00238 −1.13477 COL4A6 collagen, type IV, alpha 6 0.004113 −1.13473 BMP7 bone morphogenetic protein 7 0.005776 −1.13444 — — 0.008419 −1.13443 — — 0.007353 −1.13442 SOSTDC1 sclerostin domain containing 1 0.001856 −1.13439 SOX14 SRY (sex determining region 0.001541 −1.13438 Y)-box 14 TAS2R9 taste receptor, type 2, member 9 0.002889 −1.13437 LPHN2 latrophilin 2 0.009349 −1.13418 — — 0.0099 −1.13418 — — 0.007172 −1.13409 MAP1A microtubule-associated protein 1A 0.004384 −1.13404 OSGIN2 Oxidative stress induced growth 0.009721 −1.13398 inhibitor family member 2 SLC10A2 solute carrier family 10 0.006712 −1.13395 (sodium/bile acid cotransporter family), member 2 FAM13C family with sequence similarity 0.005974 −1.13385 13, member C EMX1 empty spiracles homeobox 1 0.005643 −1.13366 FLJ40330 hypothetical LOC645784 0.005033 −1.13365 CHI3L1 chitinase 3-like 1 (cartilage 0.002657 −1.13357 glycoprotein-39) — — 0.002091 −1.1335 CDH16 cadherin 16, KSP-cadherin 0.004017 −1.13345 SPRR1A small proline-rich protein 1A 0.00177 −1.13344 LOX lysyl oxidase 0.008602 −1.13331 — — 0.009241 −1.13331 CALCB calcitonin-related polypeptide 0.005526 −1.13322 beta GABBR2 gamma-aminobutyric acid 0.003986 −1.1332 (GABA) B receptor, 2 CPB2 carboxypeptidase B2 (plasma) 0.004188 −1.13308 RASL11B RAS-like, family 11, member B 0.007069 −1.1329 CCDC81 coiled-coil domain containing 0.009508 −1.13288 81 RUNX1 runt-related transcription 0.006825 −1.13281 factor 1 CPA1 carboxypeptidase A1 0.002754 −1.13221 (pancreatic) CLCNKA /// chloride channel Ka /// chloride 0.001569 −1.13213 CLCNKB channel Kb FHL5 four and a half LIM domains 5 0.008016 −1.13211 THSD7A thrombospondin, type I, domain 0.001208 −1.1321 containing 7A TFAP2C transcription factor AP-2 0.004298 −1.13184 binding protein 2 gamma) SPAG11B sperm associated antigen 11B 0.005305 −1.1317 CAP2 CAP, adenylate cyclase- 0.002715 −1.13166 associated protein, 2 (yeast) PODNL1 podocan-like 1 0.00498 −1.13165 SSX4 /// synovial sarcoma, X breakpoint 0.009142 −1.13163 SSX4B 4 /// synovial sarcoma, X breakpoint 4B — — 0.008421 −1.13155 G6PC glucose-6-phosphatase, 0.006788 −1.13144 catalytic subunit RPE65 retinal pigment epithelium- 0.00168 −1.13112 specific protein 65 kDa TMEM222 transmembrane protein 222 0.003611 −1.13108 — — 0.0082 −1.13098 — — 0.000935 −1.13097 KDR kinase insert domain receptor (a 0.002995 −1.13074 type III receptor tyrosine kinase) — — 0.004838 −1.13055 CHP2 calcineurin B homologous 0.00539 −1.13026 protein 2 GPR64 G protein-coupled 64 0.001932 −1.13023 TPM2 tropomyosin 2 (beta) 0.008933 −1.13017 TCEB3B transcription elongation factor 0.006753 −1.13005 B polypeptide 3B (elongin A2) E2F5 E2F transcription factor 5, 0.001129 −1.13001 p130-binding IL5RA interleukin 5 receptor, alpha 0.003392 −1.12982 AOC3 amine oxidase, copper 0.000247 −1.12972 containing 3 (vascular adhesion protein 1) ABCF3 ATP-binding cassette, sub- 0.004992 −1.12966 family F (GCN20), member 3 CPN2 carboxypeptidase N, 0.006009 −1.12966 polypeptide 2 ACE angiotensin 1 converting 0.00879 −1.12948 enzyme (peptidyl-dipeptidase A) 1 NRP2 neuropilin 2 0.008745 −1.12938 INPP5J inositol polyphosphate-5- 0.007608 −1.12935 phosphatase J SMAD9 SMAD family member 9 0.006141 −1.1293 FAM155A family with sequence similarity 0.005057 −1.12928 155, member A GART phosphoribosylglycinamide 0.00165 −1.12917 formyltransterase, phosphoribosylglycinamide synthetase, phos PIR pirin (iron-binding nuclear 0.004128 −1.12911 protein) ZNF467 Zinc finger protein 467 0.006009 −1.12907 ITSN2 intersectin 2 0.001473 −1.12903 NR1D1 /// nuclear receptor subfamily 1, 0.001964 −1.12896 THRA group D, member 1 /// thyroid hormone receptor, alpha (er RP11-35N6.1 plasticity related gene 3 0.005452 −1.12885 LAMB1 laminin, beta 1 0.006026 −1.12864 EPHB3 EPH receptor B3 0.003783 −1.12857 — — 0.008156 −1.12856 PLA2R1 phospholipase A2 receptor 1, 0.005834 −1.12854 180 kDa RAPGEF4 Rap guanine nucleotide 0.008542 −1.12853 exchange factor (GEF) 4 DNAJC8 DnaJ (Hsp40) homolog, 0.007393 −1.12851 (subfamily C, member 8 ARSJ arylsulfatase family, member J 0.002634 −1.12845 TRIM49 tripartite motif-containing 49 0.002053 −1.12832 IL9 interleukin 9 0.003046 −1.12812 GC group-specific component 0.001817 −1.12797 (vitamin D binding protein) IL12B interleukin 12B (natural killer 0.006181 −1.12764 cell stimulatory factor 2, cytotoxic lymphocyte maturat CDH2 cadherin 2, type 1, N-cadherin 0.00855 −1.12758 (neuronal) ATXN3L ataxin 3-like 0.006981 −1.12737 BTF3L1 basic transcription factor 3, 0.008187 −1.12701 like 1 pseudogene CCL19 chemokine (C-C motif) ligand 19 0.006791 −1.12696 BICC1 bicaudal C homolog 1 0.007006 −1.12695 (Drosophila) FAM186A family with sequence similarity 0.00559 −1.1268 186, member A PTPRF protein tyrosine phosphatase, 0.004195 −1.12674 receptor type, F TRPC4 transient receptor potential 0.009479 −1.12666 cation channel, subfamily C, member 4 TCL6 T-cell leukemia/lymphoma 6 0.009932 −1.12663 CYP4A22 cytochrome P450, family 4, 0.004269 −1.12654 subfamily A, polypeptide 22 FUT6 fucosyltransferase 6 (alpha (1,3) 0.001302 −1.12636 fucosyltransferase) MUC1 mucin 1, cell surface associated 0.008714 −1.12624 DKFZP434B2016 /// similar to hypothetical protein 0.002252 −1.12623 LOC643313 LOC284701 /// similar to hypothetical protein LOC284701 — — 0.005094 −1.12618 LDHA lactate dehydrogenase A 0.009545 −1.12609 — — 0.007472 −1.12582 — — 0.003741 −1.12572 LOC100131613 PRO1454 0.00409 −1.12556 TRIM3 tripartite motif-containing 3 0.004335 −1.12551 MLLT10 myeloid/lymphoid or mixed- 0.006971 −1.12505 lineage leukemia (trithorax homolog, Drosophila); translocate DZIP1 DAZ interacting protein 1 0.003223 −1.12501 ANKRD34C ankyrin repeat domain 34C 0.000954 −1.12484 BUB1 budding uninhibited by 0.002759 −1.12479 benzimidazoles 1 homolog (yeast) CSPG5 chondroitin sulfate 0.000873 −1.12474 proteoglycan 5 (neuroglycan C) FBLN1 fibulin 1 0.002979 −1.12464 GAD2 glutamate decarboxylase 2 0.007671 −1.12463 (pancreatic islets and brain, 65 kDa) — — 0.000944 −1.12451 CLDN1 claudin 1 0.002407 −1.12447 CHRNA3 cholinergic receptor, nicotinic, 0.006458 −1.12436 alpha 3 SCN11A sodium channel, voltage-gated, 0.003796 −1.12417 type XI, alpha subunit TEX11 testis expressed 11 0.006239 −1.12409 IL20RA interleukin 20 receptor, alpha 0.004863 −1.124 AKAP5 A kinase (PRKA) anchor 0.006577 −1.12361 protein 5 KBTBD10 kelch repeat and BTB (POZ) 0.005771 −1.12343 domain containing 10 MSTN myostatin 0.001873 −1.1234 TLL2 tolloid-like 2 0.009968 −1.12321 NACAD NAC alpha domain containing 0.000782 −1.12294 UNC93A unc-93 homolog A (C. elegans) 0.006006 −1.12294 PTGER1 prostaglandin E receptor 1 0.007003 −1.12294 (subtype EP1), 42 kDa OLAH oleoyl-ACP hydrolase 0.00896 −1.12289 NHLH2 nescient helix loop helix 2 0.001059 −1.12286 SERPINA6 serpin peptidase inhibitor, clade 0.002411 −1.12272 A (alpha-1 antiproteinase, antitrypsin), member 6 — — 0.006655 −1.12253 KRT17 keratin 17 0.003553 −1.12241 — — 0.006777 −1.12239 KCNMA1 potassium large conductance 0.0067 −1.12228 calcium-activated channel, subfamily M, alpha member 1 PRKCA protein kinase C, alpha 0.006437 −1.12198 STS steroid sulfatase (microsomal), 0.005597 −1.12182 isozyme S LAMA1 laminin, alpha 1 0.004674 −1.1216 GPR88 G protein-coupled receptor 88 0.008737 −1.1216 ACTN2 actinin, alpha 2 0.003627 −1.12157 TREH trehalase (brush-border 0.005379 −1.12152 membrane glycoprotein) AKAP4 A kinase (PRKA) anchor 0.004629 −1.12147 protein 4 DKX4 dickkopf homolog 4 0.005161 −1.1214 (Xenopus laevis) — — 0.007472 −1.12129 PRICKLE3 prickle homolog 3 (Drosophila) 0.007288 −1.12117 IRS4 insulin receptor substrate 4 0.004715 −1.12108 TRPV4 transient receptor potential 0.008105 −1.12103 cation channel, subfamily V, member 4 PCDH11Y protocadherin 11 Y-linked 0.002241 −1.121 — — 0.009044 −1.12095 APBB2 amyloid beta (A4) precursor 0.002596 −1.12093 protein-binding, family B, member 2 SLCO2A1 solute carrier organic anion 0.004733 −1.12079 transporter family, member 2A1 — — 0.00447 −1.12075 DRD2 dopamine receptor D2 0.002588 −1.12059 MTMR7 myotubularin related protein 7 0.009209 −1.12027 ZNF471 zinc finger protein 471 0.004677 −1.12005 TF transferrin 0.007274 −1.11993 NRIP2 nuclear receptor interacting 0.005607 −1.11966 protein 2 ST6GALNAC5 ST6 (alpha-N-acetyl- 0.005579 −1.11932 neuraminyl-2,3-beta-galactosyl- 1,3)-N-acetylgalactosaminide alpha-2 COMT Catechol-O-methyltransterase 0.007202 −1.11926 — — 0.008063 −1.11915 — — 0.005963 −1.11891 — — 0.001254 −1.11889 PAH phenylalanine hydroxylase 0.002401 −1.11852 LRRC19 leucine rich repeat containing 19 0.003683 −1.11836 PRKAR1B protein kinase, cAMP- 0.007626 −1.11835 dependent, regulatory, type I, beta HPR haptoglobin-related protein 0.005044 −1.11829 PRDM5 PR domain containing 5 0.006648 −1.11821 — — 0.008206 −1.11819 NCRNA00120 non-protein coding RNA 120 0.004933 −1.11814 LOC79999 hypothetical LOC79999 0.008297 −1.11814 ITSN2 intersectin 2 0.004428 −1.118 CACNB2 calcium channel, voltage- 0.008677 −1.11798 dependent, beta 2 subunit GPR98 G protein-coupled receptor 98 0.003265 −1.11788 PREX2 phosphatidylinositol-3,4,5- 0.00758 −1.11779 trisphosphate-dependent Rac exchange factor 2 FAM182B family with sequence similarity 0.008506 −1.11758 182, member B LAMA4 laminin, alpha 4 0.001859 −1.11742 — — 0.008182 −1.117 ARVCF armadillo repeat gene deletes in 0.004203 −1.11699 velocardiofacial syndrome HAS2 hyaluronan synthase 2 0.005988 −1.11699 YOD1 YOD1 OTU deubiquinating 0.007323 −1.11668 enzyme 1 homolog (S. cerevisiae) — — 0.003067 −1.11636 PPP2R3A protein phosphatase 2 (formerly 0.00874 −1.11635 2A), regulatory subunit B″, alpha COL4A1 collagen, type IV, alpha 1 0.002703 −1.11621 — — 0.005114 −1.11613 RBM12B RNA binding motif protein 12B 0.004522 −1.11612 TNFRSF11B tumor necrosis factor receptor 0.009363 −1.11609 superfamily, member 11b GSTA3 glutathione S-transferase alpha 3 0.009885 −1.11598 FAM66D family with sequence similarity 0.007508 −1.11588 66, member D OR10H2 olfactory receptor, family 10, 0.001279 −1.11576 subfamily H, member 2 PTHLH parathyroid hormone-like 0.003579 −1.1157 hormone ZNF674 zinc finger family member 674 0.007146 −1.11565 — — 0.004948 −1.11555 KRT19 keratin 19 0.005928 −1.11545 — — 0.006606 −1.11543 ACCN2 amiloride-sensitive cation 0.006168 −1.11533 channel 2, neuronal COL6A1 Collagen, type VI, alpha 1 0.006453 −1.11496 — — 0.007286 −1.11496 LOC100288442 /// hypothetical LOC100288442 /// 0.008735 −1.11485 LOC100289169 /// hypothetical protein LOC728888 /// LOC100289169 /// similar to LOC729602 /// acyl-CoA NPIPL2 /// NPIPL3 /// PDXDC2 SLC37A1 solute carrier family 37 0.00935 −1.11481 (glycerol-3-phosphate transporter), member 1 ATP6V1B1 ATPase, H+ transporting, 0.006862 −1.11475 lysosomal 56/58 kDa, V1 subunit B1 PTN pleiotrophin 0.009862 −1.11456 ABI3BP ABI family, member 3 (NESH) 0.004323 −1.11452 binding protein HR44 Hr44 antigen 0.002042 −1.11417 ZNF324B /// zinc finger protein 324B /// zinc 0.00485 −1.11417 ZNF584 finger protein 584 HOXD13 homeobox D13 0.005052 −1.11415 ADH6 alcohol dehydrogenase 6 (class V) 0.00011 −1.11405 IFNA8 interferon, alpha 8 0.004318 −1.1136 — — 0.001609 −1.1135 — — 0.002312 −1.11325 MYOZ2 myozenin 2 0.009469 −1.11325 NFATC4 nuclear factor of activated T- 0.008681 −1.11245 cells, cytoplasmic, calcineurin- dependent 4 ADAMTS7 ADAM metallopeptidase with 0.007469 −1.11244 thrombospondin type 1 motif, 7 FOXL1 forkhead box L1 0.009415 −1.11184 GPR17 G protein-coupled receptor 17 0.009308 −1.11183 SLC18A3 solute carrier family 18 0.006308 −1.11131 (vesicular acetylcholine), member 3 MYH6 myosin, heavy chain 6, cardiac 0.005188 −1.11125 muscle, alpha BOK BCL2-related ovarian killer 0.008744 −1.111 FGA fibrinogen alpha chain 0.006323 −1.11088 TEAD4 TEA domain family member 4 0.008474 −1.11075 — — 0.005611 −1.11074 GRM1 glutamate receptor, 0.003649 −1.11073 metabotropic 1 — — 0.008379 −1.11041 EDNRA endothelin receptor type A 0.00586 −1.11035 C8orf79 chromosome 8 open reading 0.008561 −1.11003 frame 79 METTL7A methyltransferase like 7A 0.004255 −1.10991 FOLH1 folate hydrolase (prostate- 0.002431 −1.10932 specific membrane antigen) 1 RAD54L RAD54-like (S. cerevisiae) 0.007758 −1.10898 — — 0.003086 −1.10888 — — 0.006615 −1.10851 SOX11 SRY (sex determining region 0.007605 −1.10851 Y)-box 11 CNOT3 CCR4-NOT transcription 0.006753 −1.10843 complex, subunit 3 NTS neurotensin 0.008975 −1.10791 MAPK12 mitogen-activated protein 0.001821 −1.10765 kinase 12 DOCK6 dedicator of cytokinesis 6 0.004973 −1.10674 DNAJC6 DnaJ (Hsp40) homolog, 0.008411 −1.10661 subfamily C, member 6 HS3ST3A1 heparan sulfate (glucosamine) 0.002138 −1.10659 3-O-sulfotransferase 3A1 — — 0.009792 −1.10575 LOC728395 /// testis specific protein, Y-linked 0.005872 −1.10572 TSPY1 /// 1-like /// testis specific protein, TSPY3 Y-linked 1 /// te PTH parathyroid hormone 0.00392 −1.10538 — — 0.004436 −1.10502 LAMB4 laminin, beta 4 0.008445 −1.10472 ALDOB aldolase B, fructose- 0.00586 −1.10469 bisphosphate FLG filaggrin 0.007077 −1.10448 MLANA melan-A 0.007622 −1.10421 UBE2D4 ubiquitin-conjugating enzyme 0.005409 −1.10409 E2D 4 (putative) LOC100287483 transcription elongation factor 0.007954 −1.10403 B (SIII), polypeptide I pseudogene KRT20 keratin 20 0.00756 −1.10399 — — 0.009136 −1.10295 POU1F1 POU class 1 homeobox 1 0.009389 −1.10165 SLCO1B3 solute carrier organic anion 0.003628 −1.10159 transporter family, member 1B3 CLTA Clathrin, light chain (Lca) 0.009895 −1.09903 MECOM MDS1 and EVI1 complex locus 0.009639 −1.09815 C8orf71 chromosome 8 open reading 0.005004 −1.09779 frame 71 SULT2A1 sulfotransferase, family, 0.006809 −1.09766 cytosolic, 2A, dehydroepiandrosterone (DHEA)-preferring, membe C6orf10 chromosome 6 open reading 0.007231 −1.09608 frame 10 — — 0.00835 −1.09349 SLC27A6 solute carrier family 27 (fatty 0.007873 −1.09267 transporter), member 6 PRKD1 protein kinase D1 0.00074 −1.09164 SYNPO2L synaptopodin 2-like 0.003229 −1.0912 THPO thrombopoietin 0.008285 −1.09086 GABRR1 gamma-aminobutyric acid 0.008683 −1.09024 (GABA) receptor, rho 1 CFTR cystic fibrosis transmembrane 0.003801 −1.0898 conductance regulator (ATP- binding cassette sub-family C, PPP2R3A protein phosphatase 2 (formerly 0.005056 −1.08882 2A), regulatory subunit B″, alpha DCBLD2 discoidin, CUB and LCCL 0.008379 −1.08262 domain containing 2 — — 0.008713 −1.08123 ANP32A /// acidic (leucine-rich) nuclear 0.007633 −1.07373 ANP32C /// phosphoprotein 32 family, ANP32D /// member A /// acidic (leucine-ri LOC723972 XYLT1 xylosyltransferase I 0.002463 1.33229 STAB1 stabilin 1 0.002614 1.46208 STAB1 stabilin 1 0.004388 1.52209 SASH1 SAM and SH3 domain 0.000209 1.64433 containing 1 PID1 phosphotyrosine interaction 0.008082 1.65163 domain containing 1 FUCA1 fucosidase, alpha-L-1, tissue 0.00028 1.67342 SASH1 SAM and SH3 domain 0.000586 2.01341 containing 1 LRRN3 leucine rich repeat neuronal 3 0.00066 2.52567 LRRN3 leucine rich repeat neuronal 3 0.000927 2.54705

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What is claimed is:
 1. A method of predicting clinical responsiveness to laquinimod therapy in a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome, the method comprising evaluating expression of a biomarker in the subject, so as to thereby predict clinical responsiveness to laquinimod, wherein the biomarker is a gene associated with inflammatory response, a gene associated with cellular movement, a gene associated with cell signaling, a gene associated with cell development, a gene associated with hematological system, or a combination thereof.
 2. The method of claim 1, further comprising predicting positive clinical responsiveness to laquinimod if the biomarker is up-regulated in the subject.
 3. The method of claim 2, wherein the subject is naïve to laquinimod.
 4. The method of claim 1, further comprising predicting positive clinical responsiveness to laquinimod if the biomarker suppressed in the subject.
 5. The method of claim 4, wherein the subject has previously received periodic laquinimod administration.
 6. The method of claim 5, wherein the subject has received periodic laquinimod administration for at least one month, for at least 6 months, for at least 12 months, or for at least 24 months.
 7. The method of any one of claims 1-6, wherein the gene associated with inflammatory response is a gene associated with or involved in TGFb signaling, IL-12 signaling, the pathway of adhesion of phagocytes, chemotaxis of neutrophils, transmigration of leukocytes, cavcolar mediated endocytosis, clathrin mediated endocytosis, and/or leukocyte extravasation signaling.
 8. The method of any one of claims 1-7, wherein the gene associated with cellular movement is a gene associated with or involved in adhesion and migration of phagocytes, chemotaxis of neutrophils, transmigration of leukocytes, invasion of cells, adhesion of cells, and/or leukocyte extravasation signaling.
 9. The method of any one of claims 1-8, wherein the gene associated with cell signaling is a gene associated with or involved in the pathway of adhesion of cells and/or neurotransmission.
 10. The method of any one of claims 1-9, wherein the gene associated with cell development is a gene associated with or involved in the pathway of G protein coupled receptor signaling, arachidonic acid metabolism and/or TGFβ signaling.
 11. The method of any one of claims 1-10, wherein the gene associated with hematological system is a gene associated with or involved in the pathway of aggregation of blood platelets, activation of blood platelets, aggregation of blood cells, coagulation of blood, intrinsic prothrombin activation pathway and/or coagulation system.
 12. The method of any one of claims 1-11, wherein the gene is TNFSF4, SELP, ITFA8, ITGB1/3/5, CXCL5/7, a BMP6 gene, ITGA2/8, ITGβ1/3/4/5/6, ITGBL1, MMP16/24/26/28, ADAM12/18/22, IL-1/1R/5/8/13/20/22R, IL-9/11/12/36, TNFRSF11A/B, IFNA4/8/10/17, TGβ, LTBP4, MEK1/2, TGFβ type 1 receptor, type II BMPR, smad1/2/3/4/5/6/8, PAI-1, CCL19, IKKg, LTBP1 or a combination thereof.
 13. The method of any one of claims 1-11, wherein the gene is ITGB1/3/5, CXCL5/7, BMP6, ITGA2/8, ITGB1/3/4/5/6, ITGBL1, MMP6/24/26/28, ADAM12/18/22, IL-5/20/22, IL-9/36, TNFRSF11A/B, TGβ, LTBP4, MEK1/2, Smad2/3/4, PAI-1, SELP, ITFA8, ITGB1/3/5, CXCL5/7, BMP6, ITGA2/8, ITGB1/3/4/5/6, ITGBL1, MMP16/24/26/28, ADAM12/18/22, IL-5/13/20/22, IL-9/11/36, TNFRSF11A/B, TGβ, LTBP4, MEK1/2, Smad1/2/3/4/5/6/8, PAI-1, CCL19, IKKg, LTBP1, Alpha tubulin, BMP4/7, MIS, TCF2, IL5R, IL13R, IL20R, ITGB2, NKTR, TEF, CLSTN2, LUC7L2, FABP7, TPTE, FSTL1, SF3B1, LIMS1, PDE5A, XPNPEP1, C5orf4, SPANXB1, SPANXB2, SPANXF1, KRT20, TBC1D1, GRHL2, C5orf4, SEPT6, KIAA1199, SSX21P, TPM1, CDC14B, USP47, MMRN1, CTNNAL1, SMOX, ALOX12, GLRA3, CA2, GUCY1B3, RFPL1, CLEC1B, GNG11, TSPAN32, RGS10, CALD1, PRKAR2B, CYP4F11, CLCA3P, CELSR3, CDC14B, TPM1, SEPT6, PRKG1, MAX, CCDC93, ARMCX6, LOC653354, TUBB2B, HIST1H2AJ, MFAP3L, LIMS1, GNB5, GPRASP1, SRRT, C1orf116, FBXO7, PPM1A, GUCY1B3, CTDSPL, GNAS, IGF2BP3, TPM1, HIST1H2BK, DLG4, WDR48, CALD1, LOC157627, GNB5, ZNF415, ASAP2, PSD3, GNAS, POPDC3, NRGN, ABL1M3, XYLT1, PTGIS, ARHGEF10, PDGFA, PGRMC1, HIST1H2AC, GNAS, CLDN5, MFAP3L, PGRMC1, MYST3, CAPRIN1, CALD1, FBXW7, DNM3, CD84, PRPF4B, RBM25, WASF3, GRAP2, SPARC, TAL1, NENF, XK, GP1BA, HLA-E, CA5A, LYVE1, MARCH6, NAT8B, TRIM58, RET, SDPR, TBXA2R, TMED10, APBA2, MYL9, POU1F1, H2BFS, HIST1H2BK, FAM12B, VCL, GSPT1, ALDOB, LOC150776, SMPD4, SLC37A1, SPARC, GNAS, TAS2R4, CALM3, POM121, POM121C, GRIK2, GREM1, TNNC2, EPS15L2, ENDOD1, RGS6, SF3B1, TMSB15A, ZBTB20, FUT9, ATP9A, MAX, HIST1H2AI, BAT2D1, ABL1, SNCA, GFI1B, CTSA, SNX13, RPA1, FLNA, XPNPEP1, KIF2A, ZBTB33, PSMD11, UBE2N, FOLR1, TSC22D1, PCNP, CELSR3, ACSBG1, RNF11, SEMA3E, MARCH2, PCDH24, SUPT5H, HLA-E, EGF, HLA-C, FLNA, CDK2AP1, LEPROT, SH3TC2, TUBA4A, MTMR1, TF, PRKD1, NAP1L1, DAB2, FUCA1, HIP1, THPO, MAP1B, PARVB, GP1BB, SEPT5, GJA4, PTGS1, GUCY1A3, HIST1H2AG, GNAS, LRBA, HYAL3, GP6, IGHG1, CYP2A13, CDC14B, MAX, KDM2A, CALD1, GNAZ, C19orf22, ARHGAP6, RHOC, RBX1, GP1BB, SEPT5, PRDX6, PRB4, FLNA, HIST1H2BF, RHBDF2, NUP205, SYT1, EGFL8, PPT2, TUBB1, TMC6, FLJ11292, NAP1L1, ALDH1A3, CSNK1E, PRUNE, COL4A3, ZNF221, ILF3, CABP5, RPA1, ARF1, HIST1H2BI, PTGS1, PRKAA1, GNB5, HIST2H4A, HIST2H4B, CYB5R3, TNS1, DCT, GMPR, ABI3BP, GNAS, SASH1, AAK1, XPO6, CTSL2, QSER1, MAP1LC3B, TBX6, CABP2, MRE11A, MAPRE2, TMC6, BDKRB2, MGLL, HRASLS, WHAMML1, WHAMML2, CLU, STC1, C6orf54, PABPN1, PDLIM1, CLU, PHF20, UBL4A, RNF115, HGD, RASGRP2, PNN, SAPS3, SFI1, GOLGA2, HIST2H2BE, SGEF, HGD, DUS1L, MPP1, HLA-E, GRB14, MMD, ZFHX4, CSNK1G2, HIST1H2BE, MPDZ, B2M, TBXA2R, CTDSPL, SNCA, CD99, POLS, MPL, HIST1H3F, SFRS8, NR5A2, ZMYM2, C6orf10, TMEM40, RNF43, PRUNE, MSH6, PLCB4, PARVB, TOX3, PKNOX1, RUFY1, SNCA, C10orf81, PDGFA, ASMT, HMGB1, CCDC90A, PROS1, hCG_1757335, RAP1B, MTSS1, GNRHR, LRRN3, MCM3AP, PLOD2, NAP1L1, PLOD2, HOXD13 CASKIN2, MFAP5, PITX2, SNCA, MYLK, PBX1, PRDX6, H3F3A, H3F3B, LOC440926, TMEM158, TRIM58, FSTL1, SNCA, TNS1, ATP1B1, C5orf4, LRP12, CTNNAL1, GEM, KIAA1466, ALDH1A2, MAP4K3, SNCA, RAB6B, PSD3, RIPK2, RAMP3, CALD1, CYP2E1, PSD3, PDLIM7, COBLL1, FUT3, SMOX, TGM2, LRRC50, CST6, OR7A17, C6orf145, DLEU2, DLEU2L, CPT2, HGF, TNS1, SPRY1, PLOD2, CD80, KYNU, BCAT1, NHLH1, AHCTF1, HOXA10, MTMR3, VAC14, CLCF1, FGF5, TAL1, SAMD14, ELL2, CHN1, SLC7A1, GRK5, PARD3, VPS37B, CYP2B6, CYP2B7P1, MALL, ALX4, SOX15, KRT5, ESPL1, STARD8, PSD3, KIAA0195, MYO9B, HIP1R, LOC100294412, EFNB1, ERN1, RHD, MFAP3L, PLA1A, POFUT2, C8orf39, CRYBB2, CYP4A1, PVRL2, CLCNKB, MRAS, NFIB, FKSG2, SLC11A2, FZR1, ZNF550, GLP1R, SLC19A1, RTN2, PAPOLA, STC1, GK, EXOSC6, RAPSN, HFE, EHD2, RIOK3, UBE2I, C15orf2, DMD, PRLH, MAP2K2, TP63, DACH1, PPP5C, SLC26A1, NUDT7, KCNJ12, ENTPD7, SLC26A, PRRG3, RGS6, ZBED2, FICD, ARHGAP1, ARHGDIA, SDHB, AMHR2, ABCA4, TCF20, BGN, CASP7, LPAR4, GNA12, CYP2W1, RAX, C4A, C4B, LOC100292046, LOC100294156, PXN, ESR2, MYL10, EFS, TFF3, SRPK1, LOC441601, BIRC5, CCT8L2, PPAP2B, CMA1, APOA2, KDELR2, ASCL3, RUNX1, BUB1, SLC6A8, HNRNPC, HNRNPCL1, LOC440563, LOC649330, RIBC2, CLIC4, RAB17, SCML2, SPINLW1, ANK1, EDA2R, HTR4, CDC42EP4, KANK2, ANK1, SYN1, DUX3, DUX4, FRG2C, HPX-2, LOC100134409, LOC652119, LOC653543, LOC653544, LOC653545, LOC728410, PKNOX2, MLLT4, APOA2, PENK, GNAT1, FURIN, SEMA6A, EGFL6, HRH1, TSPAN1, DBC1, TRPC7, GPR52, HAMP, PRSS2, GPR107, FLJ11292, FLJ20184, B34GALT1, NKX3-1, ASIP, EFCAB6, GPR20, CA5A, PLK4, TAAR5, SRPX2, CNTD2, AZGP1, TIMP3, RGS6, ADARB1, DYNC1I1, C10orf10, PDIA2, PITX3, HOXC13, LPAR3, CTRC, CTSL2, MUC8, AQP5, UGT1A1, UGT1A10, UGT1A4, UGT1A6, UGT1A8, UGT1A9, KCNQ2, CYP2A13, ZNF155, KIAA0892, ATP2A2, FGF5, FGF18, FUT2, SHROOM2, PRSS3, CREB3L1, MGAT2, PLCE1, MLXIPL, OR10H3, ABCB11, CD84, ARHGEF4, ORC1L, PCIF1, CD177, C1orf116, IFT122, C11orf20, DUSP13, C6orf208, PLA2G5, PRAMEF1, PRAMEF2, CYP4F8, KCNA1, MFAP4, SLC4A3, IL1RAPL1, SERPINE1, ZCCHC14, POLR3G, C16orf68, FLJ14100, SMCHD1, ASCL1, FOXA2, SLC23A2, KLK13, MTSS1L, DNMT3L, RREB1, DNMBP, PKLR, C1orf106, CCDC134, MTSS1, CCDC40, HOXB1, SCNN1B, SEMA4G, RAPGEFL1, MAGEL2, PLSCR2, CHD2, PLCD1, C1orf116, CHRNA2, MBP, CDC42BPA, MYF6, PI15, LOC440895, SBF1, MAST1, GLT8D2, ERBB3, LOH3CR2A, AMH, HR, RDH8, PAWR, DRD3, CCT8, PRELP, SPOCK3, EPS8L3, NXN, SEMA4G, P2RY1, AVL9, TEK, MOGAT2, KLK7, MT1E, MT1H, MT1M, CLDN18, RHBDF2, SIX1, INPP5A, KCNMB3, MAP2K5, GPD1, LPO, LOC729143, MPRIP, WNT7A, RARG, CDH7, MBNL2, RASGRP2, RBMY2FP, MASP1, CASR, EGR4, APOC2, HECW1, HOXB3, IRF5, NNMT, AOC2, ESRRG, LPIN1, ACOT11, CCDC33, MBD2, ZNF323, NTRK2, TMEM151B3, GPLD1, LENEP, HNF1B, NXPH3, ALDH1A3, PHF20L1, CKM, PARD6B, CRYGB, HAB1, LARGE, RAB40C, MPL, CHIT1, METTL10, DUS4L, PNLIPRP1, ELL, ST8SIA5, GRIN2B, MC4R, RTDR1, HDAC6, KCNJ13, CPSF1, SPANXC, CNOT4, LAMA2, SLC1A6, ABCA2, KLK11, GFRA3, CYP3A4, SLC1A3, ATP2B2, APBB2, VPS45, GHRHR, HOXD4, PRPH, ADCY2, LEFTY2, CYP1B1, PCP4, C8B, RANBP3, PDE6H, TRIM15, VGLL1, TRIM3, CRKL, ADH7, PSG3, GPR153, MFAP2, FGF13, NAPA, ALDH3A1, MCM10, TLE4, ITPR3, CCDC87, C9orf7, ACTC1, OBSL1, MAP2, CRYM, RNF122, SST, HLA-DRB6, SLC22A17, HSPG2, HIP1, GRIK2, UNKL, GPR144, KIR3DX1, NARFL, UCP3, PLXNA2, BTN1A1, ERCC4, CIITA, EGFR, KRT33A, CLTB, B3GALT5, AP3M2, GJC1, MYO3A, ARHGAP1, PPP2R3A, CLIC4, C20orf195, SIGLEC8, GPRC5A, CACNB1, MYL10, PRLR, OR2S2, NCR2, CHAF1B, EYA3, CDS1, FBXL18, ACTL6B, ZNF821, C16orf71, HBBP1, PLXNA1, CDC45L, MTCP1, PLCB34, PLVAP, PROX1, CYP3A43, IGHG1, RECQL5, IDUA, DLGAP4, PLXNB1, HSD17B14, FOXP3, C19orf26, EPB41L1, RBBP9, GJB4, UPK1B, CYP19A1, LOC55908, CLDN18, C2orf72, NTRK3, NRXN2, SPDEF, IGH@, IGHD, IGHG1, IGHM, LOC100289944, VSIG6, ACRV1, PHLDB1, SORBS1, HAPLN2, FABP3, EFS, ACVR1B, CHST3, UGT2A1, UGT2A2, TAF1, MT4, MFAP3, ETV5, UBQLN3, TBX10, GJB1, ABO, SPINK5, ATAD4, CDH11, CARD14, ALPP, ALPPL2, CBL, LRP4, CDKL2, SSX3, DSG2, SLC45A2, LAMA4, WFDC8, HTR7, EFNB3, TUBB2B, OR7E19P, PMS2L4, ASAP3, FRZB, PDLIM4, PVT1, TFR2, AHI1, TAF4, ADAMTSL2, CLDN4, KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL5A, KIR2DL5B, KIR2DS1, KIR2DS2, KIR2DS4, KIR2DS5, KIR3DL2, KIR3DL3, KIR3DP1, LOC727787, RAPGEF5, CRMP1, LDB3, F11, USP46, IBSP, SLC9A3, FLRT3, TRIM17, FGF17, CAMK1G, GLYR1, CSH1, NTF3, ABHD6, TRIM15, OR52A1, FGFR2, ORAI2, C17orf53, GLP1R, SLIT1, TP63, DDR1, CFTR, DIO2, LETM1, ACSM5, ACTA1, NPR1, KCND3, POPDC3, DNAH3, SPDEF, CLEC4M, SLC30A3, NAGLU, AAK1, DHX34, NNAT, AKAP9, ICMT, FAM189A1, C10orf81, MYOZ1, PKNOX2, MGC31957, PRDM11, RET, IGHG1, XPNPEP2, NTRK2, SLC25A10, NR1I2, GRM8, OR3A3, GIPR, PAH, PACRG, CLN8, ZNF2I5, TRIO, TTLL5, GRM1, PRKG1, HHLA1, LAMA3, SLC37A4, HOXC11, SLCO5A1, CA10, RRBP1, SOD3, NTRK3, CYR61, STRA6, SLC6A11, CNOT4, ATN1, BCAP29, NOVA2, RELN, LAMC2, RAD51, PRSS7, DCBLD2, TACR2, RAB11B, OR2J2, VSNL1, IFNA17, DPYSL4, MGC2889, RRBP1, POLQ, OR1A2, PURA, AIF1, CBS, NECAB2, PRKCE, NOX1, IHH, EXO1, GPRIN2, PDX1, GPR12, FAM188A, HS3ST3B1, ASCL1, ZNF484, CSH1, BCAN, DDN, DUOX2, MORN1, SLC39A2, CLCN7, RUNX2, TTYH1, ZNF280B, PAX3, LZTS1, SLC8A2, HAB1, KIF1A, ARL4D, UGT2B15, NACA2, THRB, C6orf15, GPR176, WSCD1, PLXNB3, CADM3, HAP1, CYP1A2, SPAM1, IL22RA1, CDC2L5, IRX5, PPFIA2, KDELR3, CEACAM7, KCMF1, DUOX1, CDC27, HIST2H2AA3, CAV3, APOA4, NPR3, PRG3, TBC1D22B, TUSC3, RIMS2, CYP4F12, TBXA2R, HBEGF, PSG9, PYGO1, RASGRF1, SCN2A, KLHL1, DTNB, GREM1, SNCG, C22orf24, PALM, COBLL1, DNPEP, MNS1, NFATC4, DLC1, HSPC072, MCAM, CA12, CSHL1, RPA1N, COL5A2, UGT1A8, UGT1A9, IGH@, IGHA1, IGHG1, IGHG2, IGHG3, IGHM, LOC100126583, LOC100290036, LOC100290320, LOC100293211, LOC652494, ACSM5, ALOX12P2, ERBB4, CLDN16, CIB2, GALR3, MSMB, FABP7, ATXN3, KCNJ5, TRDN, CYP3A43, BAZ2A, ACCN4, SILV, DGCR14, SEMA6C, DIO2, PTHLH, LEP, PDZRN3, RGSL1, GJA4, SLC22A6, RASGRF1, MAPRE2, PVRL1, AKAP1, POMP, SOX21, DNAH9, HOXC5, SERHL2, KIAA0485, ITSN1, B4GALT1, NEK2, NUPR1, CCDC93, EPO, CRABP2, TYRO3, GOLGA2, SEMA3F, BFSP2, NCAM1, FOLH1, SSX2, TMPRSS4, DCN, LPHN3, POU4F3, CEACAM5, BCL3, EXTL3, CCNA1, DDR2, PAX8, SOX5, POU3F1, PEX16, NUP62, SIGLEC11, ALDOB, GPC3, IGFALS, WDR25, FGF1, OSR2, ARID1A, GYPA, KLK13, PAR VB, LILRB5, RIMS2, C19orf21, HOXD1, PRSS3, FLT1, ATP6V1C1, LOX, CRYBB3, CA12, PRKG2, MASP1, LOC728395, LOC728403, TSPY1, PDCD1, GGTLC1, AQP8, KRT16, AICDA, BRD8, C1orf95, OR3A2, PFKFB2, FRZB, PAK3, MEIS2, ZSCAN2, MYH7, VWA1, LSAMP, SRC, UGT1A1, UGT1A10, UGT1A3, UGT1A4, UGT1A5, UGT1A6, UGT1A7, UGT1A8, UGT1A9, DIO1, TADA3L, NFASC, CALCRL, NBLA00301, MAB2 L1, FBXO42, COL10A1, CFB, SNX7, FOXN1, SRY, HLF, CLCA3P, DAZ1, DAZ2, DAZ3, DAZ4, GPR3, TMPRSS11E, EMID1, KCNMB2, MUC5AC, SORT1, HIF3A, MAPK4, TCP11L1, ZZEF1, DCAF7, DMWD, CLCA2, VAC14, CSPG5, STMN2, MLLT4, GALNT14, FGF12, MFAP5, SUMO3, HTR3A, GDF5, TSSK1B, CYP2A7P1, MARK1, ATP1B2, TBX6, PAX8, IL1R1, RALYL, OR2B2, TAAR3, C12orf32, IGHG1, LOC642131, DICER1, GLRA3, PPARD, HSPA4L, WNT2, VIPR2, CYP2C9, SRPX2, IGSF1, ALPK3, TFPI, KCNS3, MARCH8, FRMD4B, TACR3, FIGF, PDCD6, TNN, SPANXB1, SPANXB2, SPANXF1, RHBDD3, SPP2, PDE10A, ZNF224, FGL1, PGAM2, CADM4, APOBEC2, SLC9A5, GNAT1, ARHGEF16, SMARCA2, DNAH9, RBM26, WNT2B, KCNK2, NPBWR2, SP2, TMPRSS11D, DENND2A, TNIP3, STC1, DOCK6, ADAM5P, SYDE1, TNPO2, LRTM1, USH1C, PDE12, SRCAP, OR10J1, OR2H2, KCNJ8, RP11-257K9.7, DOCK5, TPD52L1, PAEP, GGA2, PHLDA3, HES2, MLL, CHRNA6, CIB2, PTPRF, TM7SF4, DAZ1, DAZ2, DAZ3, DAZ4, ALX1, OR2F1, OR2F2, PLAT, HGC6.3, WNT11, PGK2, SNAI2, COL4A6, PRUNE2, ANKS1B, LOC81691, FERMT2, TIMP3, CST8, CAPN6, IDUA, GPR32, AKR1B10, GRHL2, FBXO24, HSF4, IGHG1, HCN2, LRP12, ARHGEF15, UGT1A1, UGT1A10, UGT1A7, UGT1A8, GUCA2A, ITIH1, EGFR, UGT1A1, UGT1A10, UGT1A3, UGT1A4, UGT1A5, UGT1A6, UGT1A7, UGT1A8, UGT1A9, MYOG, TMSB15A, TLX1, EDNRA, LOC100289791, MDFI, ZER1, MYH15, CDH20, GPR63, LOC440345, LOC440354, LOC595101, LOC641298, SMG1, HOXC10, KRTAP1-1, ARSD, CPLX3, LMAN1L, IFNA4, ABCC1, SEMA3E, MRE11A, C1QL1, LIPF, TRIM9, BBOX1, LRRC17, WNT2B, CYP3A4, SI, ANO3, OBSL1, CHRD, MSX2, PSG1, FAM107A, LRRC37B2, ANKLE2, PAX2, UNC5B, ADCYAP1R1, HFE, SYT1, GJC2, LOC100293871, FGF8, ACRV1, NRXN1, GDPD2, RGS4, CELA2A, IFNW1, MLNR, RNF17, LAD1, GLRA2, RASL12, MAGOH2, C6orf54, ZNF214, IKBKG, AP4E1, ZNRF4, OSBPL10, C1orf175, TTC4, PCDHB3, ADRBK1, ITSN1, XAGE1A, XAGE1B, XAGE1C, XAGE1D, XAGE1E, CDH22, FARP2, MYT1, TNC, MUC5AC, SLC6A15, PP14571, SMR3A, SMR3B, RXRG, SNX1, GLP1R, C6orf155, ATP1A2, TFAP4, PNPLA2, DIRAS3, ANO2, TACSTD2, MCM3AP, IL13RA2, TRIM10, RTEL1, PRRX2, TSHB, TIMELESS, FMO1, KIF18A, KIAA1199, CALB2, MFAP3L, PTGER3, EPAS1, SQSTM1, TSPY1, CPM, DLGAP1, CYP4F11, TLX3, PCDHA10, TAOK2, ERC1, TBX2, KALRN, DICER1, PAPPA, KIF5A, DNAJC22, OTUB1, KIAA1644, SEZ6L2, PCNXL2, HMHB1, ERG, SNTB2, GJA5, AGTR2, GJA3, GCK, LRRC61, CNTF, ZFP91, ZFP91-CNTF, PDLIM4, MPPED2, IFNA10, ACTN2, VGLL1, GJA9, LDLR, ANK2, COL1A1, TIMP3, OTOF, AGXT, GLI2, TRMT61A, FOXD2, TMEM212, DENND2A, B3GALT1, SPAG11A, PRDM4, TF, ELF5, GSC2, EPB41L4B, GYG2, LYZL6, DCHS2, OBP2A, OBP2B, ANGPTL3, MYH11, NES, SLC17A1, RBM15B, CSH1, HTR5A, CYP3A7, HTR2A, KCNV2, TOX3, CLOCK, MAGEA6, FAM12A, COL4A3, S1PR2, NAT8, ACE2, SLC22A6, SLC13A2, MYH4, APBB2, RAP1GAP, SHOX2, SLCO1A2, ETV1, MAGEA12, PLA2G6, ADRA1A, SYT5, GPR161, SEMA3F, CYP3A43, HOMER2, KCNJ5, PPL, COL17A1, CSHL1, C9orf116, PARK2, UGT2B15, CDK6, FAM174B, CELA2A, CELA2B, SPDEF, EPB41, GAB1, SMR3A, PDE6G, COL5A1, ABCA6, DMD, CYLC2, CIDEA, RAG2, HIST1H2BN, FMO6P, MAOA, ANKRD53, HAPLN1, MT1M, EHD2, GAD2, CRISP2, CSN2, SULT1C2, PCDHGA3, SSX3, FGFR2, GPR161, ATN1, CHD5, A4GALT, MYBPH, CSHL1, NCAPH2, CAPN9, CNGB1, BCAM, DRD5, NR5A2, TEF, ELAVL2, DGKB, HTR7P, RHAG, GH2, COL4A6, BMP7, SOSTDC1, SOX14, TAS2R9, LPHN2, MAP1A, OSGIN2, SLC10A2, FAM13C, EMX1, FLJ40330, CHI3L1, CDH16, SPRR1A, LOX, CALCB, GABBR2, CPB2, RASL11B, CCDC81, RUNX1, CPA1, CLCNKA, CLCNKB, FHL5, THSD7A, TFAP2C, SPAG11B, CAP2, PODNL1, SSX4, SSX4B, G6PC, RPE65, TMEM222, KDR, CHP2, GPR64, TPM2, TCEB3B, E2F5, IL5RA, AOC3, ABCF3, CPN2, ACE, NRP2, INPP5J, SMAD9, FAM155A, GART, PIR, ZNF467, ITSN2, NR1D1, THRA, RP11-35N6.1, LAMB1, EPHB3, PLA2R1, RAPGEF4, DNAJC8, ARSJ, TRIM49, GC, CDH2, ATXN3L, BTF3L1, BICC1, FAM186A, PTPRF, TRPC4, TCL6, CYP4A22, FUT6, MUC1, DKFZP434B2016, LOC643313, LDHA, LOC100131613, TRIM3, MLLT10, DZIP1, ANKRD34C, BUB1, CSPG5, FBLN1, GAD2, CLDN1, CHRNA3, SCN11A, TEX11, IL20RA, AKAP5, KBTBD10, MSTN, TLL2, NACAD, UNC93A, PTGER1, OLAH, NHLH2, SERPINA6, KRT117, KCNMA1, PRKCA, STS, LAMA1, GPR88, ACTN2, TREH, AKAP4, DKK4, PRICKLE3, IRS4, TRPV4, PCDH11Y, APBB2, SLCO2A1, DRD2, MTMR7, ZNF471, TF, NRIP2, ST6GALNAC5, COMT, PAH, LRRC19, PRKAR1B, HPR, PRDM5, NCRNA00120, LOC79999, ITSN2, CACNB2, GPR98, PREX2, FAM182B, LAMA4, ARVCF, HAS2, YOD1, PPP2R3A, COL4A1, RBM12B, GSTA3, FAM66D, OR10H2, PTHLH, ZNF674, KRT19, ACCN2, COL6A1, LOC100288442, LOC100289169, LOC728888, LOC729602, NPIPL2, NPIPL3, PDXDC2, SLC37A1, ATP6V1B1, ABI3BP, HR44, ZNF324B, ZNF584, HOXD13, ADH6, IFNA8, MYOZ2, NFATC4, ADAMTS7, FOXL1, GPR17, SLC18A3, MYH6, BOK, FGA, TEAD4, GRM1, EDNRA, C8orf79, METTL7A, FOLH1, RAD54L, SOX11, CNOT3, NTS, MAPK12, DOCK6, DNAJC6, HS3ST3A1, LOC728395, TSPY1, TSPY3, PTH, LAMB4, ALDOB, FLG, MLANA, UBE2D4, LOC100287483, KRT20, POU1F1, SLCO1B3, CLTA, MECOM, C8orf11, SULT2A1, C6orf10, SLC27A6, PRKD1, SYNPO2L, THPO, GABRR1, CFTR, PPP2R3A, DCBLD2, ANP32A, ANP32C, ANP32D, LOC723972, XYLT1, STAB1, STAB1, SASH1, PID1, FUCA1, SASH1, LRRN3, LRRN3 or a combination thereof.
 14. A method of treating a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome with laquinimod, comprising the steps of: a) determining whether the subject is a laquinimod responder by evaluating expression of a biomarker in the subject, and b) administering to the subject an amount of laquinimod effective to treat the subject only if the subject is identified as a laquinimod responder, so as to thereby treat the subject, wherein the biomarker is a gene associated with inflammatory response, a gene associated with cellular movement, a gene associated with cell signaling, a gene associated with cell development, a gene associated with hematological system, or a combination thereof.
 15. A method for treating a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome comprising the steps of: a) administering to the subject a therapeutically effective amount of laquinimod, b) determining whether the subject is a laquinimod responder by evaluating expression of a biomarker in the subject; and c) administering to the subject an amount of laquinimod effective to treat the subject only if the subject is identified as a laquinimod responder, or modifying the administration of laquinimod to the subject if the subject is not identified as a laquinimod responder, so as to thereby treat the subject, wherein the biomarker is a gene associated with inflammatory response, a gene associated with cellular movement, a gene associated with cell signaling, a gene associated with cell development, a gene associated with hematological system, or a combination thereof.
 16. The method of claims 14 and 15, wherein the subject is identified as a laquinimod responder if the biomarker is up-regulated in the subject.
 17. The method of claims 14 and 15, wherein the subject is identified as a laquinimod responder if the biomarker is suppressed in the subject.
 18. The method of any one of claims 14-17, wherein the gene associated with inflammatory response is a gene associated with or involved in TGFb signaling, IL-12 signaling, the pathway of adhesion of phagocytes, chemotaxis of neutrophils, transmigration of leukocytes, caveolar mediated endocytosis, clathrin mediated endocytosis, and/or leukocyte extravasation signaling.
 19. The method of any one of claims 14-18, wherein the gene associated with cellular movement is a gene associated with or involved in adhesion and migration of phagocytes, chemotaxis of neutrophils, transmigration of leukocytes, invasion of cells, adhesion of cells, and/or leukocyte extravasation signaling.
 20. The method of any one of claims 14-19, wherein the gene associated with cell signaling is a gene associated with or involved in the pathway of adhesion of cells and/or neurotransmission.
 21. The method of any one of claims 14-20, wherein the gene associated with cell development is a gene associated with or involved in the pathway of G protein coupled receptor signaling, arachidonic acid metabolism and/or TGFβ signaling.
 22. The method of any one of claims 14-21, wherein the gene associated with hematological system is a gene associated with or involved in the pathway of aggregation of blood platelets, activation of blood platelets, aggregation of blood cells, coagulation of blood, intrinsic prothrombin activation pathway and/or coagulation system.
 23. The method of any one of claims 14-22, wherein the gene is TNFSF4, SELP, ITFA8, ITGB1/3/5, CXCL5/7, a BMP6 gene, ITGA2/8, ITGβ1/3/4/5/6, ITGBL1, MMP16/24/26/28, ADAM12/18/22, IL-1/1R/5/8/13/20/22R, IL-9/11/12/36, TNFRSF11A/B, IFNA4/8/10/17, TGβ, LTBP4, MEK1/2, TGFβ type 1 receptor, type II BMPR, smad1/2/3/4/5/6/8, PAI-1, CCL19, IKKg, LTBP1 or a combination thereof.
 24. The method of any one of claims 14-22, wherein the gene is ITGB1/3/5, CXCL5/7, BMP6, ITGA2/8, ITGB1/3/4/5/6, ITGBL1, MMP16/24/26/28, ADAM12/18/22, IL-5/20/22, IL-9/36, TNFRSF11A/B, TGβ, LTBP4, MEK1/2, Smad2/3/4, PAI-1, SELP, ITFA8, ITGB1/3/5, CXCL5/7, BMP6, ITGA2/8, ITGB1/3/4/5/6, ITGBL1, MMP16/24/26/28, ADAM12/18/22, IL-5/13/20/22, IL-9/11/36, TNFRSF11A/B, TGβ, LTBP4, MEK1/2, Smad1/2/3/4/5/6/8, PAI-1, CCL19, IKKg, LTBP1, Alpha tubulin, BMP4/7, MIS, TCF2, IL5R, IL13R, IL20R, ITGB2, NKTR, TEF, CLSTN2, LUC7L2, FABP7, TPTE, FSTL1, SF3B1, LIMS1, PDE5A, XPNPEP1, C5orf4, SPANXB1, SPANXB2, SPANXF1, KRT20, TBC1D1, GRHL2, C5orf4, SEPT6, KIAA1199, SSX21P, TPM1, CDC14B, USP47, MMRN1, CTNNAL1, SMOX, ALOX12, GLRA3, CA2, GUCY1B3, RFPL1, CLEC1B, GNG11, TSPAN32, RGS10, CALD1, PRKAR2B, CYP4F11, CLCA3P, CELSR3, CDC14B, TPM1, SEPT6, PRKG1, MAX, CCDC93, ARMCX6, LOC653354, TUBB2B, HIST1H2AJ, MFAP3L, LIMS1, GNB5, GPRASP1, SRRT, C1orf116, FBXO7, PPM1A, GUCY1B3, CTDSPL, GNAS, IGF2BP3, TPM1, HIST1H2BK, DLG4, WDR48, CALD1, LOC157627, GNB5, ZNF415, ASAP2, PSD3, GNAS, POPDC3, NRGN, ABL1M3, XYLT1, PTGIS, ARHGEF10, PDGFA, PGRMC1, HIST1H2AC, GNAS, CLDN5, MFAP3L, PGRMC1, MYST3, CAPRIN1, CALD1, FBXW7, DNM3, CD84, PRPF4B, RBM25, WASF3, GRAP2, SPARC, TAL1, NENF, XK, GP1BA, HLA-E, CA5A, LYVE1, MARCH6, NAT8B, TRIM58, RET, SDPR, TBXA2R, TMED10, APBA2, MYL9, POU1F1, H2BFS, HIST1H2BK, FAM12B, VCL, GSPT1, ALDOB, LOC150776, SMPD4, SLC37A1, SPARC, GNAS, TAS2R4, CALM3, POM121, POM121C, GRIK2, GREM1, TNNC2, EPS15L2, ENDOD1, RGS6, SF3B1, TMSB15A, ZBTB20, FUT9, ATP9A, MAX, HIST1H2AI, BAT2D1, ABL1, SNCA, GFI1B, CTSA, SNX13, RPA1, FLNA, XPNPEP1, KIF2A, ZBTB33, PSMD11, UBE2N, FOLR1, TSC22D1, PCNP, CELSR3, ACSBG1, RNF11, SEMA3E, MARCH2, PCDH24, SUPT5H, HLA-E, EGF, HLA-C, FLNA, CDK2AP1, LEPROT, SH3TC2, TUBA4A, MTMR1, TF, PRKD1, NAP1L1, DAB2, FUCA1, HIP1, THPO, MAP1B, PARVB, GP1BB, SEPT5, GJA4, PTGS1, GUCY1A3, HIST1H2AG, GNAS, LRBA, HYAL3, GP6, IGHG1, CYP2A13, CDC14B, MAX, KDM2A, CALD1, GNAZ, C19orf22, ARHGAP6, RHOC, RBX1, GP1BB, SEPT5, PRDX6, PRB4, FLNA, HIST1H2BF, RHBDF2, NUP205, SYT1, EGFL8, PPT2, TUBB1, TMC6, FLJ11292, NAP1L1, ALDH1A3, CSNK1E, PRUNE, COL4A3, ZNF221, ILF3, CABP5, RPA1, ARF1, HIST1H2BI, PTGS1, PRKAA1, GNB5, HIST2H4A, HIST2H4B, CYB5R3, TNS1, DCT, GMPR, ABI3BP, GNAS, SASH1, AAK1, XPO6, CTSL2, QSER1, MAP1LC3B, TBX6, CABP2, MRE11A, MAPRE2, TMC6, BDKRB2, MGLL, HRASLS, WHAMML1, WHAMML2, CLU, STC1, C6orf54, PABPN1, PDLIM1, CLU, PHF20, UBL4A, RNF115, HGD, RASGRP2, PNN, SAPS3, SFI1, GOLGA2, HIST2H2BE, SGEF, HGD, DUS1L, MPP1, HLA-E, GRB14, MMD, ZFHX4, CSNK1G2, HIST1H2BE, MPDZ, B2M, TBXA2R, CTDSPL, SNCA, CD99, POLS, MPL, HIST1H3F, SFRS8, NR5A2, ZMYM2, C6orf10, TMEM40, RNF43, PRUNE, MSH6, PLCB4, PARVB, TOX3, PKNOX1, RUFY1, SNCA, C10orf81, PDGFA, ASMT, HMGB1, CCDC90A, PROS1, hCG_1757335, RAP1B, MTSS1, GNRHR, LRRN3, MCM3AP, PLOD2, NAP1L1, PLOD2, HOXD13 CASKIN2, MFAP5, PITX2, SNCA, MYLK, PBX1, PRDX6, H3F3A, H3F3B, LOC440926, TMEM158, TRIM58, FSTL1, SNCA, TNS1, ATP1B1, C5orf4, LRP12, CTNNAL1, GEM, KIAA1466, ALDH1A2, MAP4K3, SNCA, RAB6B, PSD3, RIPK2, RAMP3, CALD1, CYP2E1, PSD3, PDLIM7, COBLL1, FUT3, SMOX, TGM2, LRRC50, CST6, OR7A17, C6orf145, DLEU2, DLEU2L, CPT2, HGF, TNS11, SPRY1, PLOD2, CD80, KYNU, BCAT1, NHLH1, AHCTF1, HOXA10, MTMR3, VAC14, CLCF1, FGF5, TAL1, SAMD14, ELL2, CHN1, SLC7A1, GRK5, PARD3, VPS37B, CYP2B6, CYP2B7P1, MALL, ALX4, SOX15, KRT5, ESPL1, STARD8, PSD3, KIAA0195, MYO9B, HIP1R, LOC100294412, EFNB1, ERN1, RHD, MFAP3L, PLA1A, POFUT2, C8orf39, CRYBB2, CYP4A11, PVRL2, CLCNKB, MRAS, NFIB, FKSG2, SLC11A2, FZR1, ZNF550, GLP1R, SLC19A1, RTN2, PAPOLA, STC1, GK, EXOSC6, RAPSN, HFE, EHD2, RIOK3, UBE2I, C15orf2, DMD, PRLH, MAP2K2, TP63, DACH1, PPP5C, SLC26A1, NUDT7, KCNJ12, ENTPD7, SLC26A1, PRRG3, RGS6, ZBED2, FICD, ARHGAP1, ARHGDIA, SDHB, AMHR2, ABCA4, TCF20, BGN, CASP7, LPAR4, GNA12, CYP2W1, RAX, C4A, C4B, LOC100292046, LOC100294156, PXN, ESR2, MYL10, EFS, TFF3, SRPK1, LOC441601, BIRC5, CCT8L2, PPAP2B, CMA1, APOA2, KDELR2, ASCL3, RUNX1, BUB1, SLC6A8, HNRNPC, HNRNPCL1, LOC440563, LOC649330, RIBC2, CLIC4, RAB17, SCML2, SPINLW1, ANK1, EDA2R, HTR4, CDC42EP4, KANK2, ANK1, SYN1, DUX3, DUX4, FRG2C, HPX-2, LOC100134409, LOC652119, LOC653543, LOC653544, LOC653545, LOC728410, PKNOX2, MLLT4, APOA2, PENK, GNAT1, FURIN, SEMA6A, EGFL6, HRH1, TSPAN1, DBC1, TRPC7, GPR52, HAMP, PRSS2, GPR107, FLJ11292, FLJ20184, B4GALT1, NKX3-1, ASIP, EFCAB6, GPR20, CA5A, PLK4, TAAR5, SRPX2, CNTD2, AZGP1, TIMP3, RGS6, ADARB1, DYNC1I1, C10orf10, PDIA2, PITX3, HOXC13, LPAR3, CTRC, CTSL2, MUC8, AQP5, UGT1A1, UGT1A10, UGT1A4, UGT1A6, UGT1A8, UGT1A9, KCNQ2, CYP2A13, ZNF155, KIAA0892, ATP2A2, FGF5, FGF18, FUT2, SHROOM2, PRSS3, CREB3L1, MGAT2, PLCE1, MLXIPL, OR10113, ABCB11, CD84, ARHGEF4, ORC1L, PCIF1, CD177, C1orf116, IFT122, C11orf20, DUSP13, C6orf208, PLA2G5, PRAMEF1, PRAMEF2, CYP4F8, KCNA1, MFAP4, SLC4A3, IL1RAPL1, SERPINE1, ZCCHC14, POLR3G, C16orf68, FLJ14100, SMCHD1, ASCL1, FOXA2, SLC23A2, KLK13, MTSS1L, DNMT3L, RREB1, DNMBP, PKLR, C1orf106, CCDC134, MTSS1, CCDC40, HOXB1, SCNN1B, SEMA4G, RAPGEFL1, MAGEL2, PLSCR2, CHD2, PLCD1, C1orf116, CHRNA2, MBP, CDC42BPA, MYF6, PI15, LOC440895, SBF1, MAST1, GLT8D2, ERBB3, LOH3CR2A, AMH, HR, RDH8, PAWR, DRD3, CCT8, PRELP, SPOCK3, EPS8L3, NXN, SEMA4G, P2RY1, AVL9, TEK, MOGAT2, KLK7, MT1E, MT1H, MT1M, CLDN18, RHBDF2, SIX1, INPP5A, KCNMB3, MAP2K5, GPD1, LPO, LOC729143, MPRIP, WNT7A, RARG, CDH7, MBNL2, RASGRP2, RBMY2FP, MASP1, CASR, EGR4, APOC2, HECW1, HOXB3, IRF5, NNMT, AOC2, ESRRG, LPIN1, ACOT11, CCDC33, MBD2, ZNF323, NTRK2, TMEM151B, GPLD1, LENEP, HNF1B, NXPH3, ALDH1A3, PHF20L1, CKM, PARD6B, CRYGB, HAB1, LARGE, RAB40C, MPL, CHIT1, METTL10, DUS4L, PNLIPRP1, ELL, ST8SIA5, GRIN2B, MC4R, RTDR1, HDAC6, KCNJ13, CPSF1, SPANXC, CNOT4, LAMA2, SLC1A6, ABCA2, KLK11, GFRA3, CYP3A4, SLC1A3, ATP2B2, APBB2, VPS45, GHRHR, HOXD4, PRPH, ADCY2, LEFTY2, CYP1B1, PCP4, C8B, RANBP3, PDE6H, TRIM15, VGLL1, TRIM3, CRKL, ADH7, PSG3, GPR153, MFAP2, FGF13, NAPA, ALDH3A1, MCM10, TLE4, ITPR3, CCDC87, C9orf7, ACTC1, OBSL1, MAP2, CRYM, RNF122, SST, HLA-DRB6, SLC22A17, HSPG2, HIP1, GRIK2, UNKL, GPR144, KIR3DX1, NARFL, UCP3, PLXNA2, BTN1A1, ERCC4, CIITA, EGFR, KRT33A, CLTB, B3GALT5, AP3M2, GJC1, MYO3A, ARHGAP1, PPP2R3A, CLIC4, C20orf195, SIGLEC8, GPRC5A, CACNB1, MYL10, PRLR, OR2S2, NCR2, CHAF1B, EYA3, CDS1, FBXL18, ACTL6B, ZNF821, C16orf71, HBBP1, PLXNA1, CDC45L, MTCP1, PLCB4, PLVAP, PROX1, CYP3A43, IGHG1, RECQL5, IDUA, DLGAP4, PLXNB1, HSD17B14, FOXP3, C19orf26, EPB4 L1, RBBP9, GJB4, UPK1B, CYP19A1, LOC55908, CLDN18, C2orf72, NTRK3, NRXN2, SPDEF, IGH@, IGHD, IGHG1, IGHM, LOC100289944, VSIG6, ACRV1, PHLDB1, SORBS1, HAPLN2, FABP3, EFS, ACVR1B, CHST3, UGT2A1, UGT2A2, TAF1, MT4, MFAP3, ETV5, UBQLN3, TBX10, GJB1, ABO, SPINK5, ATAD4, CDH11, CARD14, ALPP, ALPPL2, CBL, LRP4, CDKL2, SSX3, DSG2, SLC45A2, LAMA4, WFDC8, HTR7, EFNB3, TUBB2B, OR7E19P, PMS2L4, ASAP3, FRZB, PDLIM4, PVT1, TFR2, AHI1, TAF4, ADAMTSL2, CLDN4, KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL5A, KIR2DL5B, KIR2DS1, KIR2DS2, KIR2DS4, KIR2DS5, KIR3DL2, KIR3DL3, KIR3 DP1, LOC727787, RAPGEF5, CRMP1, LDB3, F11, USP46, IBSP, SLC9A3, FLRT3, TRIM17, FGF17, CAMK1G, GLYR1, CSH1, NTF3, ABHD6, TRIM15, OR52A1, FGFR2, ORAI2, C17orf53, GLP1R, SLIT1, TP63, DDR1, CFTR, DIO2, LETM1, ACSM5, ACTA1, NPR1, KCND3, POPDC3, DNAH3, SPDEF, CLEC4M, SLC30A3, NAGLU, AAK1, DHX34, NNAT, AKAP9, ICMT, FAM189A1, C10orf81, MYOZ1, PKNOX2, MGC31957, PRDM11, RET, IGHG1, XPNPEP2, NTRK2, SLC25A10, NR1I2, GRM8, OR3A3, GIPR, PAH, PACRG, CLN8, ZNF215, TRIO, TTLL5, GRM1, PRKG1, HHLA1, LAMA3, SLC37A4, HOXC11, SLCO5A1, CA10, RRBP1, SOD3, NTRK3, CYR61, STRA6, SLC6A11, CNOT4, ATN1, BCAP29, NOVA2, RELN, LAMC2, RAD51, PRSS7, DCBLD2, TACR2, RAB11B, OR2J2, VSNL1, IFNA17, DPYSL4, MGC2889, RRBP1, POLQ, OR1A2, PURA, AIF1, CBS, NECAB2, PRKCE, NOX1, IHH, EXO1, GPRIN2, PDX1, GPR12, FAM188A, HS3ST3B1, ASCL1, ZNF484, CSH1, BCAN, DDN, DUOX2, MORN1, SLC39A2, CLCN7, RUNX2, TTYH1, ZNF280B, PAX3, LZTS1, SLC8A2, HAB1, KIF1A, ARL4D, UGT2B15, NACA2, THRB, C6orf15, GPR176, WSCD1, PLXNB3, CADM3, HAP1, CYP1A2, SPAM1, IL22RA1, CDC2L5, IRX5, PPFIA2, KDELR3, CEACAM7, KCMF1, DUOX1, CDC27, HIST2H2AA3, CAV3, APOA4, NPR3, PRG3, TBC1D22B, TUSC3, RIMS2, CYP4F12, TBXA2R, HBEGF, PSG9, PYGO1, RASGRF1, SCN2A, KLHL1, DTNB, GREM1, SNCG, C22orf24, PALM, COBLL1, DNPEP, MNS1, NFATC4, DLC1, HSPC072, MCAM, CA12, CSHL1, RPA1N, COL5A2, UGT1A8, UGT1A9, IGH@, IGHA1, IGHG1, IGHG2, IGHG3, IGHM, LOC100126583, LOC100290036, LOC100290320, LOC100293211, LOC652494, ACSM5, ALOX12P2, ERBB4, CLDN16, CIB2, GALR3, MSMB, FABP7, ATXN3, KCNJ5, TRDN, CYP3A43, BAZ2A, ACCN4, SILV, DGCR14, SEMA6C, DIO2, PTHLH, LEP, PDZRN3, RGSL1, GJA4, SLC22A6, RASGRF1, MAPRE2, PVRL1, AKAP1, POMP, SOX21, DNAH9, HOXC5, SERHL2, KIAA0485, ITSN1, B4GALT1, NEK2, NUPR1, CCDC93, EPO, CRABP2, TYRO3, GOLGA2, SEMA3F, BFSP2, NCAM1, FOLH1, SSX2, TMPRSS4, DCN, LPHN3, POU4F3, CEACAM5, BCL3, EXTL3, CCNA1, DDR2, PAX8, SOX5, POU3F1, PEX16, NUP62, SIGLEC11, ALDOB, GPC3, IGFALS, WDR25, FGF1, OSR2, ARID1A, GYPA, KLK13, PARVB, LILRB5, RIMS2, C19orf21, HOXD1, PRSS3, FLT1, ATP6V1C1, LOX, CRYBB3, CA112, PRKG2, MASP1, LOC728395, LOC728403, TSPY11, PDCD1, GGTLC1, AQP8, KRT16, AICDA, BRD8, C1orf95, OR3A2, PFKFB2, FRZB, PAK3, MEIS2, ZSCAN2, MYH7, VWA1, LSAMP, SRC, UGT1A1, UGT1A10, UGT1A3, UGT1A4, UGT1A5, UGT1A6, UGT1A7, UGT1A8, UGT1A9, DIO1, TADA3L, NFASC, CALCRL, NBLA00301, MAB21L1, FBXO42, COL10A1, CFB, SNX7, FOXN1, SRY, HLF, CLCA3P, DAZ1, DAZ2, DAZ3, DAZ4, GPR3, TMPRSS11E, EMID1, KCNMB2, MUC5AC, SORT1, HIF3A, MAPK4, TCP11L1, ZZEF1, DCAF7, DMWD, CLCA2, VAC14, CSPG5, STMN2, MLLT4, GALNT14, FGF12, MFAP5, SUMO3, HTR3A, GDF5, TSSK1B, CYP2A7P1, MARK1, ATP1B2, TBX6, PAX8, IL1R1, RALYL, OR2B2, TAAR3, C12orf32, IGHG1, LOC642131, DICER1, GLRA3, PPARD, HSPA4L, WNT2, VIPR2, CYP2C9, SRPX2, IGSF1, ALPK3, TFPI, KCNS3, MARCH8, FRMD4B, TACR3, FIGF, PDCD6, TNN, SPANXB1, SPANXB2, SPANXF1, RHBDD3, SPP2, PDE10A, ZNF224, FGL1, PGAM2, CADM4, APOBEC2, SLC9A5, GNAT1, ARHGEF16, SMARCA2, DNAH9, RBM26, WNT2B, KCNK2, NPBWR2, SP2, TMPRSS11D, DENND2A, TNIP3, STC1, DOCK6, ADAM5P, SYDE1, TNPO2, LRTM1, USH1C, PDE12, SRCAP, OR10J1, OR2H2, KCNJ8, RP11-257K9.7, DOCK5, TPD52L1, PAEP, GGA2, PHLDA3, HES2, MLL, CHRNA6, CIB2, PTPRF, TM7SF4, DAZ1, DAZ2, DAZ3, DAZ4, ALX1, OR2F1, OR2F2, PLAT, HGC6.3, WNT11, PGK2, SNAI2, COL4A6, PRUNE2, ANKS1B, LOC81691, FERMT2, TIMP3, CST8, CAPN6, IDUA, GPR32, AKR1B10, GRHL2, FBXO24, HSF4, IGHG1, HCN2, LRP12, ARHGEF15, UGT1A1, UGT1A10, UGT1A7, UGT1A8, GUCA2A, ITIH1, EGFR, UGT1A1, UGT1A10, UGT1A3, UGT1A4, UGT1A5, UGT1A6, UGT1A7, UGT1A8, UGT1A9, MYOG, TMSB15A, TLX1, EDNRA, LOC100289791, MDFI, ZER1, MYH15, CDH20, GPR63, LOC440345, LOC440354, LOC595101, LOC641298, SMG1, HOXC10, KRTAP1-1, ARSD, CPLX3, LMAN1L, IFNA4, ABCC11, SEMA3E, MRE11A, C1QL1, LIPF, TRIM9, BBOX1, LRRC17, WNT2B, CYP3A4, SI, ANO3, OBSL1, CHRD, MSX2, PSG1, FAM107A, LRRC37B2, ANKLE2, PAX2, UNC5B, ADCYAP1R1, HFE, SYT1, GJC2, LOC100293871, FGF8, ACRV1, NRXN1, GDPD2, RGS4, CELA2A, IFNW1, MLNR, RNF17, LAD1, GLRA2, RASL12, MAGOH2, C6orf54, ZNF214, IKBKG, AP4E1, ZNRF4, OSBPL10, C1orf175, TTC4, PCDHB3, ADRBK1, ITSN1, XAGE1A, XAGE1B, XAGE1C, XAGE1D, XAGE1E, CDH22, FARP2, MYT1, TNC, MUC5AC, SLC6A15, PP14571, SMR3A, SMR3B, RXRG, SNX1, GLP1R, C6orf155, ATP1A2, TFAP4, PNPLA2, DIRAS3, ANO2, TACSTD2, MCM3AP, IL13RA2, TRIM10, RTEL1, PRRX2, TSHB, TIMELESS, FMO1, KIF18A, KIAA1199, CALB2, MFAP3L, PTGER3, EPAS1, SQSTM1, TSPY1, CPM, DLGAP1, CYP4F11, TLX3, PCDHA10, TAOK2, ERC1, TBX2, KALRN, DICER1, PAPPA, KIF5A, DNAJC22, OTUB1, KIAA1644, SEZ6L2, PCNXL2, HMHB1, ERG, SNTB2, GJA5, AGTR2, GJA3, GCK, LRRC61, CNTF, ZFP91, ZFP91-CNTF, PDLIM4, MPPED2, IFNA10, ACTN2, VGLL1, GJA9, LDLR, ANK2, COL1A1, TIMP3, OTOF, AGXT, GLI2, TRMT61A, FOXD2, TMEM2I2, DENND2A, B3GALT1, SPAG11A, PRDM4, TF, ELF5, GSC2, EPB41 L4B, GYG2, LYZL6, DCHS2, OBP2A, OBP2B, ANGPTL3, MYH11, NES, SLC17A1, RBM15B, CSH1, HTR5A, CYP3A7, HTR2A, KCNV2, TOX3, CLOCK, MAGEA6, FAM12A, COL4A3, S1PR2, NAT8, ACE2, SLC22A6, SLC13A2, MYH4, APBB2, RAP1GAP, SHOX2, SLCO1A2, ETV1, MAGEA12, PLA2G6, ADRA1A, SYT5, GPR161, SEMA3F, CYP3A43, HOMER2, KCNJ5, PPL, COL17A1, CSHL1, C9orf116, PARK2, UGT2B15, CDK6, FAM174B3, CELA2A, CELA2B, SPDEF, EPB41, GAB1, SMR3A, PDE6G, COL5A1, ABCA6, DMD, CYLC2, CIDEA, RAG2, HIST1H2BN, FMO6P, MAOA, ANKRD53, HAPLN1, MT1M, EHD2, GAD2, CRISP2, CSN2, SULT1C2, PCDHGA3, SSX3, FGFR2, GPR161, ATN1, CHD5, A4GALT, MYBPH, CSHL1, NCAPH2, CAPN9, CNGB1, BCAM, DRD5, NR5A2, TEF, ELAVL2, DGKB, HTR7P, RHAG, GH2, COL4A6, BMP7, SOSTDC1, SOX14, TAS2R9, LPHN2, MAP1A, OSGIN2, SLC10A2, FAM13C, EMX1, FLJ40330, CHI3L1, CDH16, SPRR1A, LOX, CALCB, GABBR2, CPB2, RASL11B, CCDC81, RUNX1, CPA1, CLCNKA, CLCNKB, FHL5, THSD7A, TFAP2C, SPAG11B, CAP2, PODNL1, SSX4, SSX4B, G6PC, RPE65, TMEM222, KDR, CHP2, GPR64, TPM2, TCEB3B, E2F5, IL5RA, AOC3, ABCF3, CPN2, ACE, NRP2, INPP5J, SMAD9, FAM155A, GART, PIR, ZNF467, ITSN2, NR1D1, THRA, RP11-35N6.1, LAMB1, EPHB3, PLA2R1, RAPGEF4, DNAJC8, ARSJ, TRIM49, GC, CDH2, ATXN3L, BTF3L1, BICC1, FAM186A, PTPRF, TRPC4, TCL6, CYP4A22, FUT6, MUC1, DKFZP434B2016, LOC643313, LDHA, LOC100131613, TRIM3, MLLT10, DZIP1, ANKRD34C, BUB1, CSPG5, FBLN1, GAD2, CLDN1, CHRNA3, SCN11A, TEX11, IL20RA, AKAP5, KBTBD10, MSTN, TLL2, NACAD, UNC93A, PTGER1, OLAH, NHLH2, SERPINA6, KRT17, KCNMA1, PRKCA, STS, LAMA1, GPR88, ACTN2, TREH, AKAP4, DKK4, PRICKLE3, IRS4, TRPV4, PCDH11Y, APBB2, SLCO2A1, DRD2, MTMR7, ZNF471, TF, NRIP2, ST6GALNAC5, COMT, PAH, LRRC19, PRKAR1B, HPR, PRDM5, NCRNA00120, LOC79999, ITSN2, CACNB2, GPR98, PREX2, FAM182B, LAMA4, ARVCF, HAS2, YOD1, PPP2R3A, COL4A1, RBM12B, GSTA3, FAM66D, OR10H2, PTHLH, ZNF674, KRT119, ACCN2, COL6A1, LOC100288442, LOC100289169, LOC728888, LOC729602, NPIPL2, NPIPL3, PDXDC2, SLC37A1, ATP6V1B1, ABI3BP, HR44, ZNF324B, ZNF584, HOXD13, ADH6, IFNA8, MYOZ2, NFATC4, ADAMTS7, FOXL1, GPR17, SLC18A3, MYH6, BOK, FGA, TEAD4, GRM1, EDNRA, C8orf79, METTL7A, FOLH1, RAD54L, SOX11, CNOT3, NTS, MAPK12, DOCK6, DNAJC6, HS3ST3A1, LOC728395, TSPY1, TSPY3, PTH, LAMB4, ALDOB, FLG, MLANA, UBE2D4, LOC100287483, KRT20, POU1F1, SLCO1B3, CLTA, MECOM, C8orf71, SULT2A1, C6orf10, SLC27A6, PRKD1, SYNPO2L, THPO, GABRR1, CFTR, PPP2R3A, DCBLD2, ANP32A, ANP32C, ANP32D, LOC723972, XYLT1, STAB1, STAB1, SASH1, PID1, FUCA1, SASH1, LRRN3, LRRN3 or a combination thereof.
 25. The method of any one of claims 14-24, wherein laquinimod is administered orally.
 26. The method of any one of claims 14-25, wherein laquinimod is administered daily.
 27. The method of any one of claims 14-26, wherein laquinimod is administered at a dose of less than 0.6 mg/day, of 0.1-40.0 mg/day, 0.1-2.5 mg/day, 0.25-2.0 mg/day, 0.5-1.2 mg/day, 0.25 mg/day, 0.3 mg/day, 0.5 mg/day, 0.6 mg/day, 1.0 mg/day, 1.2 mg/day, 1.5 mg/day or 2.0 mg/day.
 28. The method of any one of claims 14-27, wherein the subject is naïve to laquinimod.
 29. The method of any one of claims 14-27, wherein the subject has been previously administered laquinimod.
 30. The method of any one of claims 14-27, wherein the subject has been previously administered a multiple sclerosis drug other than laquinimod.
 31. The method of any one of claims 14-30, wherein the step of evaluating expression of the biomarker comprises normalization of the subject's gene expression.
 32. The method of any one of claims 14-31, wherein the step of evaluating expression of the biomarker comprises comparing expression level in the subject relative to a reference value.
 33. The method of claim 32, wherein the reference value is based on the level of expression of the biomarker in a laquinimod Non-Responder population.
 34. The method of claim 32, wherein the reference value is based on the level of expression of the biomarker in a healthy control population.
 35. The method of any one of claims 32-34, wherein the subject is identified as a laquinimod responder if expression of the biomarker is higher than a reference value.
 36. The method of any one of claims 32-34, wherein the subject is identified as a laquinimod responder if expression level of the biomarker is lower than a reference value.
 37. The method of any one of claims 1-36, wherein expression of the biomarker is evaluated in the blood of the subject.
 38. The method of claim 37, wherein expression of the biomarker is evaluated in the peripheral blood mononuclear cells (PBMCs) of the subject.
 39. The method of any one of claims 14-38, wherein expression of the biomarker is evaluated prior to treatment with laquinimod.
 40. The method of any one of claims 14-38, wherein expression of the biomarker is evaluated after beginning treatment with laquinimod.
 41. The method of claim 40, wherein expression of the biomarker is evaluated one month, 6 months, 12 months or 24 months after beginning treatment with laquinimod.
 42. The method of any one of claims 14-41, wherein if the subject is identified as a laquinimod responder, the subject is thereafter administered a pharmaceutical composition comprising laquinimod and a pharmaceutically acceptable carrier as monotherapy.
 43. The method of any one of claims 14-41, wherein if the subject is identified as a laquinimod responder, the subject is thereafter administered a pharmaceutical composition comprising laquinimod and a pharmaceutically acceptable carrier in combination with another multiple sclerosis drug.
 44. The method of any one of claims 14-43, wherein if the subject is identified as a laquinimod non-responder, the subject is thereafter administered a multiple sclerosis drug which is not laquinimod.
 45. The method of any one of claims 1-44, wherein the subject is a human patient.
 46. Laquinimod for use in treating a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome, wherein the subject has been identified as a laquinimod responder.
 47. A pharmaceutical composition comprising an amount of laquinimod for use in treating a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome, wherein the subject has been identified as a laquinimod responder.
 48. Laquinimod for use in treating a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome, wherein expression of a biomarker in the subject is up-regulated and the biomarker is a gene associated with inflammatory response, a gene associated with cellular movement, a gene associated with cell signaling, a gene associated with cell development, a gene associated with hematological system, or a combination thereof.
 49. A pharmaceutical composition comprising an amount of laquinimod for use in treating a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome, wherein expression of a biomarker in the subject is up-regulated and the biomarker is a gene associated with inflammatory response, a gene associated with cellular movement, a gene associated with cell signaling, a gene associated with cell development, a gene associated with hematological system, or a combination thereof.
 50. Laquinimod for use in treating a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome, wherein expression of a biomarker in the subject is suppressed and the biomarker is a gene associated with inflammatory response, a gene associated with cellular movement, a gene associated with cell signaling, a gene associated with cell development, a gene associated with hematological system, or a combination thereof.
 51. A pharmaceutical composition comprising an amount of laquinimod for use in treating a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome, wherein expression of a biomarker in the subject is suppressed and the biomarker is a gene associated with inflammatory response, a gene associated with cellular movement, a gene associated with cell signaling, a gene associated with cell development, a gene associated with hematological system, or a combination thereof.
 52. A therapeutic package for dispensing to, or for use in dispensing to, a subject identified as a laquinimod responder afflicted with multiple sclerosis or presenting a clinically isolated syndrome, which comprises: a) one or more unit doses, each such unit dose comprising an amount of laquinimod, and b) a finished pharmaceutical container therefor, said container containing said unit dose or unit doses, said container further containing or comprising labeling directing the use of said package in the treatment of said subject.
 53. A therapeutic package for dispensing to, or for use in dispensing to, a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome, which comprises: a) one or more unit doses, each such unit dose comprising an amount of laquinimod, and b) a finished pharmaceutical container therefor, said container containing said unit dose or unit doses, said container further containing or comprising labeling directing the use of said package in the treatment of said subject, wherein expression of a biomarker in the subject is suppressed or up-regulated and the biomarker is a gene associated with inflammatory response, a gene associated with cellular movement, a gene associated with cell signaling, a gene associated with cell development, a gene associated with hematological system, or a combination thereof. 